Multicyclic amino acid derivatives and methods of their use

ABSTRACT

Compounds of formulae I and II are disclosed, as well as compositions comprising them and methods of their use to treat, prevent and manage serotonin-mediated diseases and disorders:

This application claims priority to U.S. patent application No.60/754,955, filed Dec. 29, 2005.

1. FIELD OF THE INVENTION

This invention relates to multicyclic compounds, compositions comprisingthem, and their use in the treatment, prevention and management ofdiseases and disorders.

2. BACKGROUND

The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involvedin multiple central nervous facets of mood control and in regulatingsleep, anxiety, alcoholism, drug abuse, food intake, and sexualbehavior. In peripheral tissues, serotonin is reportedly implicated inthe regulation of vascular tone, gut motility, primary hemostasis, andcell-mediated immune responses. Walther, D. J., et al., Science 299:76(2003).

The enzyme tryptophan hydroxylase (TPH) catalyzes the rate limiting stepof the biosynthesis of serotonin. Two isoforms of TPH have beenreported: TPH1, which is expressed in the periphery, primarily in thegastrointestinal (GI) tract; and TPH2, which is expressed in the brain.Id. The isoform TPH1 is encoded by the tph1 gene; TPH2 is encoded by thetph2 gene. Id.

Mice genetically deficient for the tph1 gene (“knockout mice”) have beenreported. In one case, the mice reportedly expressed normal amounts ofserotonin in classical serotonergic brain regions, but largely lackedserotonin in the periphery. Id. In another, the knockout mice exhibitedabnormal cardiac activity, which was attributed to a lack of peripheralserotonin. Côté, F., et al., PNAS 100(23):13525-13530 (2003).

Because serotonin is involved in so many biochemical processes, drugsthat affect serotonin levels are often attended by adverse effects.Thus, a need exists for new ways of treating diseases and disorders thatare affected by serotonin.

3. SUMMARY OF THE INVENTION

This invention is directed, in part, to compounds of formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond(i.e., A is directly bound to D), —O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—,—C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—, —N(R₅)—, —N(R₅)C(O)N(R₅)—,—C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—, —C(R₃)NO—, —C(R₃R₄)O—,—OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —C(R₃R₄)S(O₂)—, or—S(O₂)C(R₃R₄)—; D is optionally substituted aryl or heterocycle; R₁ ishydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle,aryl, or heterocycle; R₂ is hydrogen or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R₃ is hydrogen,alkoxy, amino, cyano, halogen, hydroxyl, or optionally substitutedalkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, oroptionally substituted alkyl or aryl; each R₅ is independently hydrogenor optionally substituted alkyl or aryl; and n is 0-3.

The invention also encompassed compounds of formula II:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond(i.e., A is directly bound to D), —O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—,—C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—, —N(R₅)—, —N(R₅)C(O)N(R₅)—,—C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—, —C(R₃)NO—, —C(R₃R₄)O—,—OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —C(R₃R₄)S(O₂)—, or—S(O₂)C(R₃R₄)—; D is optionally substituted aryl or heterocycle; E isoptionally substituted aryl or heterocycle; R₁ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₂ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₃ is hydrogen, alkoxy, amino,cyano, halogen, hydroxyl, or optionally substituted alkyl; R₄ ishydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl or aryl; R₅ is hydrogen or optionally substitutedalkyl or aryl; and n is 0-3.

Particular compounds inhibit TPH (e.g., TPH1) activity.

This invention is also directed to pharmaceutical compositions and tomethods of treating, preventing and managing a variety of diseases anddisorders.

4. BRIEF DESCRIPTION OF THE FIGURE

Aspects of the invention may be understood with reference to theattached figure. FIG. 1 shows the effects of a potent TPH1 inhibitor ofthe invention in the mouse gastrointestinal tract and brain after oraladministration. All data are presented as percentage of the mean of thecontrol (vehicle-dosed) group. Error bars are S.E.M. N=5 per group. Thesymbols are *, p<0.05 vs control group. For the brain data, p=0.5,one-way ANOVA.

5. DETAILED DESCRIPTION

This invention is based, in part, on the discovery that knocking out thetph1 gene in mice significantly reduces levels of GI serotonin, yetcauses little, if any, measurable effect on the central nervous system(CNS).

This invention is also based on the discovery of compounds that inhibitTPH (e.g., TPH1). When administered to mammals, preferred compounds ofthe invention reduce serotonin levels, and may be used in the treatment,prevention and management of a wide range of diseases and disorders.

5.1. Definitions

Unless otherwise indicated, the term “alkenyl” means a straight chain,branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or2 to 6) carbon atoms, and including at least one carbon-carbon doublebond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and3-decenyl.

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms.

Alkyl moieties having from 1 to 4 carbons are referred to as “loweralkyl.” Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyland dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, andexamples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andadamantyl. Additional examples of alkyl moieties have linear, branchedand/or cyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term“alkyl” includes saturated hydrocarbons as well as alkenyl and alkynylmoieties.

Unless otherwise indicated, the term “alkoxy” means an —O-alkyl group.Examples of alkoxy groups include —OCH₃, —OCH₂CH₃, —O(CH₂)₂CH₃,—O(CH₂)₃CH₃, —O(CH₂)₄CH₃, and —O(CH₂)₅CH₃.

Unless otherwise indicated, the term “alkylaryl” or “alkyl-aryl” meansan alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or“alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or“alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain,branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2to 6) carbon atoms, and including at least one carbon-carbon triplebond. Representative alkynyl moieties include acetylenyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or anaromatic or partially aromatic ring system composed of carbon andhydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include anthracenyl, azulenyl,biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl,1,2,3,4-tetrahydro-naphthalene, and tolyl.

Unless otherwise indicated, the term “arylalkyl” or “aryl-alkyl” meansan aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the terms “biohydrolyzable amide,”“biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzablecarbonate,” “biohydrolyzable ureido” and “biohydrolyzable phosphate”mean an amide, ester, carbamate, carbonate, ureido, or phosphate,respectively, of a compound that either: 1) does not interfere with thebiological activity of the compound but can confer upon that compoundadvantageous properties in vivo, such as uptake, duration of action, oronset of action; or 2) is biologically inactive but is converted in vivoto the biologically active compound. Examples of biohydrolyzable estersinclude lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkylesters, and choline esters. Examples of biohydrolyzable amides includelower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkyl-carbonyl amides. Examples of biohydrolyzable carbamatesinclude lower alkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

Unless otherwise indicated, the phrases “disease or disorder mediated byperipheral serotonin” and “disease and disorder mediated by peripheralserotonin” mean a disease and/or disorder having one or more symptoms,the severity of which are affected by peripheral serotonin levels.

Unless otherwise indicated, the terms “halogen” and “halo” encompassfluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term “heteroalkyl” refers to an alkylmoiety (e.g., linear, branched or cyclic) in which at least one of itscarbon atoms has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise indicated, the term “heteroaryl” means an aryl moietywherein at least one of its carbon atoms has been replaced with aheteroatom (e.g., N, O or S). Examples include acridinyl,benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl,indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, andtriazinyl.

Unless otherwise indicated, the term “heteroarylalkyl” or“heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “heterocycle” refers to anaromatic, partially aromatic or non-aromatic monocyclic or polycyclicring or ring system comprised of carbon, hydrogen and at least oneheteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e.,two or more) rings fused or bound together. Heterocycles includeheteroaryls. Examples include benzo[1,3]dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl,morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl and valerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or“heterocycle-alkyl” refers to a heterocycle moiety bound to an alkylmoiety.

Unless otherwise indicated, the term “heterocycloalkyl” refers to anon-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl” or“heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to analkyl moiety.

Unless otherwise indicated, the terms “manage,” “managing” and“management” encompass preventing the recurrence of the specifieddisease or disorder, or of one or more of its symptoms, in a patient whohas already suffered from the disease or disorder, and/or lengtheningthe time that a patient who has suffered from the disease or disorderremains in remission. The terms encompass modulating the threshold,development and/or duration of the disease or disorder, or changing theway that a patient responds to the disease or disorder.

Unless otherwise indicated, the term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicacids or bases including inorganic acids and bases and organic acids andbases. Suitable pharmaceutically acceptable base addition salts includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include inorganic and organic acids such as acetic,alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art. See, e.g., Remington's Pharmaceutical Sciences,18^(th) ed. (Mack Publishing, Easton Pa.: 1990) and Remington: TheScience and Practice of Pharmacy, 19^(th) ed. (Mack Publishing, EastonPa.: 1995).

Unless otherwise indicated, the term “potent TPH1 inhibitor” is acompound that has a TPH1_IC₅₀ of less than about 10 μM.

Unless otherwise indicated, the terms “prevent,” “preventing” and“prevention” contemplate an action that occurs before a patient beginsto suffer from the specified disease or disorder, which inhibits orreduces the severity of the disease or disorder, or of one or more ofits symptoms. The terms encompass prophylaxis.

Unless otherwise indicated, the term “prodrug” encompassespharmaceutically acceptable esters, carbonates, thiocarbonates, N-acylderivatives, N-acyloxyalkyl derivatives, quaternary derivatives oftertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates,phosphate esters, metal salts and sulfonate esters of compoundsdisclosed herein. Examples of prodrugs include compounds that comprise abiohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzablecarbamate, biohydrolyzable carbonate, biohydrolyzable ester,biohydrolyzable phosphate, or biohydrolyzable ureide analog). Prodrugsof compounds disclosed herein are readily envisioned and prepared bythose of ordinary skill in the art. See, e.g., Design of Prodrugs,Bundgaard, A. Ed., Elseview, 1985; Bundgaard, H., “Design andApplication of Prodrugs,” A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.

Unless otherwise indicated, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease or condition, orone or more symptoms associated with the disease or condition, orprevent its recurrence. A prophylactically effective amount of acompound is an amount of therapeutic agent, alone or in combination withother agents, which provides a prophylactic benefit in the prevention ofthe disease. The term “prophylactically effective amount” can encompassan amount that improves overall prophylaxis or enhances the prophylacticefficacy of another prophylactic agent.

Unless otherwise indicated, the term “protecting group” or “protectivegroup,” when used to refer to part of a molecule subjected to a chemicalreaction, means a chemical moiety that is not reactive under theconditions of that chemical reaction, and which may be removed toprovide a moiety that is reactive under those conditions. Protectinggroups are well known in the art. See, e.g., Greene, T. W. and Wuts, P.G. M., Protective Groups in Organic Synthesis (3^(rd) ed., John Wiley &Sons: 1999); Larock, R. C., Comprehensive Organic Transformations(2^(nd) ed., John Wiley & Sons: 1999). Some examples include benzyl,diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl,and pthalimido.

Unless otherwise indicated, the term “pseudohalogen” refers to apolyatomic anion that resembles a halide ion in its acid-base,substitution, and redox chemistry, generally has low basicity, and formsa free radical under atom transfer radical polymerization conditions.Examples of pseudohalogens include azide ions, cyanide, cyanate,thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.

Unless otherwise indicated, the term “selective TPH1 inhibitor” is acompound that has a TPH2_IC₅₀ that is at least about 10 times greaterthan its TPH1_IC₅₀.

Unless otherwise indicated, the term “stereomerically enrichedcomposition of” a compound refers to a mixture of the named compound andits stereoisomer(s) that contains more of the named compound than itsstereoisomer(s). For example, a stereoisomerically enriched compositionof (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and(R)-butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10,95/5, and 98/2.

Unless otherwise indicated, the term “stereoisomeric mixture”encompasses racemic mixtures as well as stereomerically enrichedmixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and70/30).

Unless otherwise indicated, the term “stereomerically pure” means acomposition that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one stereocenterwill be substantially free of the opposite stereoisomer of the compound.A stereomerically pure composition of a compound having twostereocenters will be substantially free of other diastereomers of thecompound. A typical stereomerically pure compound comprises greater thanabout 80% by weight of one stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers of the compound, greater thanabout 90% by weight of one stereoisomer of the compound and less thanabout 10% by weight of the other stereoisomers of the compound, greaterthan about 95% by weight of one stereoisomer of the compound and lessthan about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

Unless otherwise indicated, the term “substituted,” when used todescribe a chemical structure or moiety, refers to a derivative of thatstructure or moiety wherein one or more of its hydrogen atoms issubstituted with an atom, chemical moiety or functional group such as,but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy,alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl),alkynyl, alkylcarbonyloxy (—OC(O)alkyl), amide (—C(O)NH-alkyl- or-alkylNHC(O)alkyl), amidinyl (—C(NH)NH-alkyl or —C(NR)NH₂), amine(primary, secondary and tertiary such as alkylamino, arylamino,arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (—NHC(O)O-alkyl-or —OC(O)NH-alkyl), carbamyl (e.g., CONH₂, as well as CONH-alkyl,CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid,carboxylic acid anhydride, carboxylic acid chloride, cyano, ester,epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl(e.g., —CCl₃, —CF₃, —C(CF₃)₃), heteroalkyl, hemiacetal, imine (primaryand secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro,oxygen (i.e., to provide an oxo group), phosphodiester, sulfide,sulfonamido (e.g., SO₂NH₂), sulfone, sulfonyl (including alkylsulfonyl,arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl,thioether) and urea (—NHCONH-alkyl-).

Unless otherwise indicated, a “therapeutically effective amount” of acompound is an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or condition, or to delay orminimize one or more symptoms associated with the disease or condition.A therapeutically effective amount of a compound is an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of a disease or condition, or enhances thetherapeutic efficacy of another therapeutic agent.

Unless otherwise indicated, the term “TPH1_IC₅₀” is the IC₅₀ of acompound for TPH1 as determined using the in vitro inhibition assaydescribed in the Examples, below.

Unless otherwise indicated, the term “TPH2_IC₅₀” is the IC₅₀ of acompound for TPH2 as determined using the in vitro inhibition assaydescribed in the Examples, below.

Unless otherwise indicated, the terms “treat,” “treating” and“treatment” contemplate an action that occurs while a patient issuffering from the specified disease or disorder, which reduces theseverity of the disease or disorder, or one or more of its symptoms, orretards or slows the progression of the disease or disorder.

Unless otherwise indicated, the term “include” has the same meaning as“include” and the term “includes” has the same meaning as “includes, butis not limited to.” Similarly, the term “such as” has the same meaningas the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted alky, aryl, orheteroaryl” has the same meaning as “optionally substituted alkyl,optionally substituted aryl, or optionally substituted heteroaryl.”

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, the two phrases “XOH, wherein X is pyridyl” and “XOH,wherein X is pyridine” are accorded the same meaning, and encompass thecompounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or the portion of the structure is to beinterpreted as encompassing all stereoisomers of it. Similarly, names ofcompounds having one or more chiral centers that do not specify thestereochemistry of those centers encompass pure stereoisomers andmixtures thereof. Moreover, any atom shown in a drawing with unsatisfiedvalences is assumed to be attached to enough hydrogen atoms to satisfythe valences. In addition, chemical bonds depicted with one solid lineparallel to one dashed line encompass both single and double (e.g.,aromatic) bonds, if valences permit.

5.2. Compounds

This invention encompasses, inter alia, compounds of formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; D is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and n is0-3.

Particular compounds are of formula I(A):

Also encompassed by the invention are compounds of formula II:

and pharmaceutically acceptable salts and solvates thereof, wherein: Ais optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; D is optionally substituted aryl orheterocycle; E is optionally substituted aryl or heterocycle; R₁ ishydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle,aryl, or heterocycle; R₂ is hydrogen or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R₃ is hydrogen,alkoxy, amino, cyano, halogen, hydroxyl, or optionally substitutedalkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, oroptionally substituted alkyl or aryl; R₅ is hydrogen or optionallysubstituted alkyl or aryl; and n is 0-3.

Particular compounds are of formula II(A):

With regard to the formulae disclosed herein (e.g., I, I(A), II andII(A)), particular compounds include those wherein A is optionallysubstituted cycloalkyl (e.g., 6-membered and 5-membered). In some, A isoptionally substituted aryl (e.g., phenyl or naphthyl). In others, A isoptionally substituted heterocycle (e.g., 6-membered and 5-membered).Examples of 6-membered heterocycles include pyridine, pyridazine,pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocyclesinclude pyrrole, imidazole, triazole, thiazole, thiophene, and furan. Insome compounds, A is aromatic. In others, A is not aromatic. In some, Ais an optionally substituted bicyclic moiety (e.g., indole, iso-indole,pyrrolo-pyridine, or napthylene).

Particular compounds are of the formula:

wherein: each of A₁ and A₂ is independently a monocyclic optionallysubstituted cycloalkyl, aryl, or heterocycle. Compounds encompassed bythis formula include those wherein A₁ and/or A₂ is optionallysubstituted cycloalkyl (e.g., 6-membered and 5-membered). In some, A₁and/or A₂ is optionally substituted aryl (e.g., phenyl or naphthyl). Inothers, A₁ and/or A₂ is optionally substituted heterocycle (e.g.,6-membered and 5-membered). Examples of 6-membered heterocycles includepyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of5-membered heterocycles include pyrrole, imidazole, triazole, thiazole,thiophene, and furan. In some compounds, A₁ and/or A₂ is aromatic. Inothers, A₁ and/or A₂ is not aromatic.

With regard to the formulae disclosed herein, particular compoundsinclude those wherein D is optionally substituted aryl (e.g., phenyl ornaphthyl). In others, D is optionally substituted heterocycle (e.g.,6-membered and 5-membered). Examples of 6-membered heterocycles includepyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of5-membered heterocycles include pyrrole, imidazole, triazole, thiazole,thiophene, and furan. In some compounds, D is aromatic. In others, D isnot aromatic. In some, D is an optionally substituted bicyclic moiety(e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).

With regard to the various formulae disclosed herein, particularcompounds include those wherein E is optionally substituted aryl (e.g.,phenyl or naphthyl). In others, E is optionally substituted heterocycle(e.g., 6-membered and 5-membered). Examples of 6-membered heterocyclesinclude pyridine, pyridazine, pyrimidine, pyrazine, and triazine.Examples of 5-membered heterocycles include pyrrole, imidazole,triazole, thiazole, thiophene, and furan. In some compounds, E isaromatic. In others, E is not aromatic. In some, E is an optionallysubstituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine,or napthylene).

With regard to the various formulae disclosed herein, particularcompounds include those wherein R₁ is hydrogen or optionally substitutedalkyl.

In some, R₂ is hydrogen or optionally substituted alkyl.

In some, n is 1 or 2.

In some, X is a bond or S. In others, X is —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—,—C(R₄)═C(R₄)—, or —C≡C—, and, for example, R₄ is independently hydrogenor optionally substituted alkyl. In others, X is —O—, —C(R₃R₄)O—, or—OC(R₃R₄)—, and, for example, R₃ is hydrogen or optionally substitutedalkyl, and R₄ is hydrogen or optionally substituted alkyl. In some, R₃is hydrogen and R₄ is trifluromethyl. In some compounds, X is —S(O₂)—,—S(O₂)N(R₅)—, —N(R₅)S(O₂)—, —C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—, and, forexample, R₃ is hydrogen or optionally substituted alkyl, R₄ is hydrogenor optionally substituted alkyl, and R₅ is hydrogen or optionallysubstituted alkyl. In others, X is —N(R₅)—, —N(R₅)C(O)N(R₅)—,—C(R₃R₄)N(R₅)—, or —N(R₅)C(R₃R₄)—, and, for example, R₃ is hydrogen oroptionally substituted alkyl, R₄ is hydrogen or optionally substitutedalkyl, and each R₅ is independently hydrogen or optionally substitutedalkyl.

Some compounds of the invention are encompassed by the formula:

wherein, for example, R₃ is trifluoromethyl. Others are encompassed bythe formula:

wherein, for example, R₃ is hydrogen.

Some compounds are encompassed by the formula:

wherein: each of Z₁, Z₂, Z₃, and Z₄ is independently N or CR₆; each R₆is independently hydrogen, cyano, halogen, OR₇, NR₈R₉, amino, hydroxyl,or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; eachR₇ is independently hydrogen or optionally substituted alkyl, alkyl-arylor alkyl-heterocycle; each R₈ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₉ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; and m is 1-4. Certain such compounds are of theformula:

Others are of the formula:

wherein, for example, R₃ is trifluoromethyl. Others are of the formula:

wherein, for example, R₃ is hydrogen.

Referring to the various formulae above, some compounds are such thatall of Z₁, Z₂, Z₃, and Z₄ are N. In others, only three of Z₁, Z₂, Z₃,and Z₄ are N. In others, only two of Z₁, Z₂, Z₃, and Z₄ are N. Inothers, only one of Z₁, Z₂, Z₃, and Z₄ is N. In others, none of Z₁, Z₂,Z₃, and Z₄ are N.

Some compounds are of the formula:

wherein: each of Z′₁, Z′₂, and Z′₃ is independently N, NH, S, O or CR₆;each R₆ is independently amino, cyano, halogen, hydrogen, OR₇, SR₇,NR₈R₉, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;each R₇ is independently hydrogen or optionally substituted alkyl,alkyl-aryl or alkyl-heterocycle; each R₈ is independently hydrogen oroptionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₉is independently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; and p is 1-3. Certain such compounds are of theformula:

Others are of the formula:

wherein, for example, R₃ is trifluoromethyl. Others are of the formula:

wherein, for example, R₃ is hydrogen.

Referring to the various formulae above, some compounds are such thatall of Z′₁, Z′₂, and Z′₃ are N or NH. In others, only two of Z′₁, Z′₂,and Z′₃ are N or NH. In others, only one of Z′₁, Z′₂, and Z′₃ is N orNH. In others, none of Z′₁, Z′₂, and Z′₃ are N or NH.

Some compounds are encompassed by the formula:

wherein: each of Z″₁, Z″₂, Z″₃, and Z″₄ is independently N or CR₁₀; eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; and each R₁₃ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain suchcompounds are of the formula:

Others are of the formula:

wherein, for example, R₃ is trifluoromethyl. Others are of the formula:

wherein, for example, R₃ is hydrogen.

Referring to the various formulae above, some compounds are such thatall of Z″₁, Z″₂, Z″₃, and Z″₄ are N. In others, only three of Z″₁, Z″₂,Z″₃, and Z″₄ are N. In others, only two of Z″₁, Z″₂, Z″₃, and Z″₄ are N.In others, only one of Z″₁, Z″₂, Z″₃, and Z″₄ is N. In others, none ofZ″₁, Z″₂, Z″₃, and Z″₄ are N.

Some compounds are of the formula:

wherein: each of Z″₁, Z″₂, Z″₃, and Z″₄ is independently N or CR₁₀; eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; and each R₁₃ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain suchcompounds are of the formula:

Others are of the formula:

wherein, for example, R₃ is trifluoromethyl. Others are of the formula:

wherein, for example, R₃ is hydrogen.

Referring to the various formulae above, some compounds are such thatall of Z″₁, Z″₂, Z″₃, and Z″₄ are N. In others, only three of Z″₁, Z″₂,Z″₃, and Z″₄ are N. In others, only two of Z″₁, Z″₂, Z″₃, and Z″₄ are N.In others, only one of Z″₁, Z″₂, Z″₃, and Z″₄ is N. In others, none ofZ″₁, Z″₂, Z″₃, and Z″₄ are N.

Some are of the formula:

the substituents of which are defined herein. Others are of the formula:

the substituents of which are defined herein. Others are of the formula:

the substituents of which are defined herein. Others are of the formula:

the substituents of which are defined herein.

Referring to the various formulae disclosed herein, particular compoundsinclude those wherein both A and E are optionally substituted phenyland, for example, X is —O—, —C(R₃R₄)O—, or —OC(R₃R₄)— and, for example,R₃ is hydrogen and R₄ is trifluoromethyl and, for example, n is 1.

With reference to the various generic chemical structures describedherein, certain embodiments of the invention are such that one or moreof the following conditions apply:

-   -   1) E and D are not both optionally substituted phenyl (i.e., E        is not phenyl optionally substituted with at least one moiety in        addition to D and the —[CH₂]_(n)— moiety, and D is not phenyl        optionally substituted with at least one moiety in addition to E        and X).    -   2) E and D are not both optionally substituted phenyl when A is        optionally substituted phenyl (i.e., A is phenyl optionally        substituted with at least one moiety in addition to X).    -   3) E and D are not both phenyl.    -   4) E and D are not both phenyl when A is optionally substituted        phenyl.    -   5) E, D and A are not all phenyl.    -   6) When E is para-phenyl (i.e., D is attached at the position        para to the —[CH₂]_(n)— moiety), and n is 1, D is not optionally        substituted pyridazin-3(2H)-one. In a specific embodiment, when        E is para-phenyl, n is 1, R₁ is —C(O) (optionally substituted        phenyl), and R₂ is H, D is not optionally substituted        pyridazin-3(2H)-one. A more specific embodiment does not        encompass compounds disclosed in international patent        application WO 05/077915.    -   7) A is not optionally substituted pyrrolidine. In a specific        embodiment, when E is para-phenyl, and n is 1, D is not        optionally substituted 2,6-dimethoxyphenyl. In another specific        embodiment, when E is para-phenyl, n is 1, X is —CH₂—, and A is        pyrrolidine, D is not optionally substituted        pyridazin-3(2H)-one. A more specific embodiment does not        encompass compounds disclosed in international patent        application WO 05/068415.    -   8) When E is para-phenyl, and n is 1, D is not optionally        substituted quinazoline. In a specific embodiment, when E is        para-phenyl, n is 1, and X is —NH— or —CH₂—, D is not optionally        substituted quinazoline. In another specific embodiment, when E        is para-phenyl, and n is 1, D is not optionally substituted        quinazoline-2,4(1H,3H)-dione. In another specific embodiment,        when E is para-phenyl, n is 1, and R₁ is —C(O) (optionally        substituted phenyl), D is not optionally substituted        quinazoline-2,4(1H,3H)-dione. A more specific embodiment does        not encompass compounds disclosed in international patent        application WO 05/061466.    -   9) When E is optionally substituted phenyl (i.e., E is phenyl        optionally substituted with moieties in addition to D and the        —[CH₂]_(n)— moiety), D is optionally substituted phenyl (i.e., D        is phenyl optionally substituted with moieties in addition to X        and E), n is 1, and X is —OCH₂—, A is not phenyl. In a specific        embodiment, when E is meta-(optionally substituted phenyl)        (i.e., E is phenyl optionally substituted with moieties in        addition to D and the —[CH₂]_(n)— moieties, and D is attached at        the position meta to the —[CH₂]_(n)— moiety), D is optionally        substituted phenyl, n is 1, and X is —OCH₂—, A is not phenyl. In        another specific embodiment, when E is meta-(optionally        substituted phenyl), D is optionally substituted phenyl, n is 1,        X is —OCH₂—, and R₂ is optionally substituted alkyl or        alkyl-aryl, A is not phenyl. In another specific embodiment,        when E is meta-(substituted phenyl) (i.e., E is phenyl        substituted with one or more moieties in addition to D and the        —[CH₂]_(n)— moiety, and D is attached at the position meta to        the —[CH₂]_(n)— moiety), D is substituted phenyl (i.e., D is        phenyl optionally substituted with at least one moiety in        addition to X and E), n is 1, and X is —OCH₂—, A is not phenyl.        A more specific embodiment does not encompass compounds        disclosed in international patent application WO 05/058943, WO        05/033129, WO 04/012816, or WO 03/106480.    -   10) When E is para-phenyl, D is phenyl, n is 1, X is not O or        —OCH₂—. In a specific embodiment, when E is para-phenyl, D is        phenyl, n is 1, and X is O or —OCH₂—, A is not cycloalkyl or        optionally substituted phenyl (i.e., phenyl optionally        substituted with at least one moiety in addition to X). In        another specific embodiment, when E is para-phenyl, D is        para-phenyl (i.e., X is attached at the position para to E) or        ortho-phenyl (i.e., X is attached at the position ortho to E), n        is 1, and X is O or —OCH₂—, A is not cycloalkyl or optionally        substituted phenyl. In another specific embodiment, when E is        para-phenyl, D is phenyl, n is 1, X is O or —OCH₂—, and R₁ is        not H, A is not cycloalkyl or optionally substituted phenyl. In        another specific embodiment, when E is para-phenyl, D is phenyl,        n is 1, X is O or —OCH₂—, R₁ is not H, and R₂ is methyl or H, A        is not cycloalkyl or optionally substituted phenyl. A more        specific embodiment does not encompass compounds disclosed in        international patent application WO 05/014534, WO 05/014533, WO        05/014532, or WO 04/014844.    -   11) When E is para-phenyl, D is ortho-phenyl, n is 1, and X is        —CH₂—, A is not piperidine. A more specific embodiment does not        encompass compounds disclosed in international patent        application WO 04/014844.    -   12) When E is para-phenyl, D is optionally substituted purine, n        is 1, and X is —CH₂—, A is not phenyl. In a specific embodiment,        when E is para-phenyl, D is optionally substituted purine, n is        1, X is —CH₂—, and at least one of R₁ and R₂ is H, A is not        phenyl. A more specific embodiment does not encompass compounds        disclosed in international patent application WO 04/094426.    -   13) When E is para-phenyl, D is optionally substituted purine, n        is 1, and X is a bond, A is not optionally substituted        tetrahydrofuran. In a specific embodiment, when E is        para-phenyl, D is optionally substituted purine, n is 1, X is        —CH₂—, and neither of R₁ and R₂ is H, A is not optionally        substituted tetrahydrofuran. A more specific embodiment does not        encompass compounds disclosed in international patent        application WO 04/094426.    -   14) When E is phenyl, D is optionally substituted phthalazine        (i.e., phthalazine optionally substituted with at least one        moiety other than E and X), and X is —CH₂—, A is not optionally        substituted pyridine (i.e., pyridine optionally substituted with        a moiety other than X). In a specific embodiment, when E is        phenyl, D is optionally substituted phthalazine, and X is —CH₂—,        A is not substituted pyridine. A more specific embodiment does        not encompass compounds disclosed in international patent        application WO 04/056798.    -   15) When E is para-(optionally substituted phenyl), D is        meta-(optionally substituted phenyl), and n is 1, X is not a        bond, —CH₂—, —CH₂O—, —NR₅—, or —CH₂NR₅—. A more specific        embodiment does not encompass compounds disclosed in        international patent application WO 04/046091.    -   16) E is not isoxazole. In a specific embodiment, when E is        isoxazole, D is para-phenyl, and n is 1, X is not —OCH₂—. In        another specific embodiment, when E is isoxazole, D is        para-phenyl, n is 1, and X is —OCH₂—, A is not optionally        substituted quinoline (i.e., quinoline optionally substituted        with one or more moieties in addition to X). A more specific        embodiment does not encompass compounds disclosed in        international patent application WO 04/043349.    -   17) When E is para-(optionally substituted phenyl), and n is 1,        D is not optionally substituted 1,4-piperazine (i.e., piperazine        optionally substituted with at least one moiety in addition to E        and X, which are bound to the nitrogen atoms at the 1 and 4        positions). In a specific embodiment, when E is para-(optionally        substituted phenyl), n is 1, D is optionally substituted        1,4-piperazine, X is not a bond or —CH₂—. A more specific        embodiment does not encompass compounds disclosed in        international patent application WO 03/089410.    -   18) D is not optionally substituted        1,1-dioxo-1,2,5-thiadiazolidine. In a specific embodiment, when        E is para-phenyl, D is not optionally substituted        1,1-dioxo-1,2,5-thiadiazolidine. In another specific embodiment,        when E is para-phenyl, n is 1, and D is optionally substituted        1,1-dioxo-1,2,5-thiadiazolidine, X is not —CH₂—. In another        specific embodiment, when E is para-phenyl, n is 1, D is        1,1-dioxo-1,2,5-thiadiazolidine-3-one, and X is —CH₂—, A is not        optionally substituted phenyl. A more specific embodiment does        not encompass compounds disclosed in international patent        application WO 03/082841.    -   19) When E is para-phenyl, and n is 1, D is not optionally        substituted quinazoline or 1,2,3,4-tetrahydroquinazoline (e.g.,        3,4-dihydroquinazolin-2(1H)-one, quinazoline-2,4(1H,3H)-dione,        2-thioxo-2,3-dihydroquinazolin-4(1H)-one, quinazolin-4(3H)-one,        or 1H-benzo[c][1,2,6]thiadiazin-4(3H)-one, any of which may be        optionally substituted with moieties in addition to E and X). In        a specific embodiment, when E is para-phenyl, n is 1, and R₁ is        2,6-dichlorobenzoyl, D is not optionally substituted optionally        substituted quinazoline or 1,2,3,4-tetrahydroquinazoline. A more        specific embodiment does not encompass compounds disclosed in        international patent application WO 03/070709 or WO 02/016329.    -   20) D is not optionally substituted piperidine. In a specific        embodiment, when E is optionally substituted pyrimidin-2(1H)-one        (i.e., pyrimidin-2(1H)-one optionally substituted with moieties        in addition to D and the —[CH₂]_(n)— moiety), and n is 1, D is        not optionally substituted piperidine. In another specific        embodiment, when E is optionally substituted        pyrimidin-2(1H)-one, n is 1, and D is optionally substituted        piperidine, X is not —CH₂— or —CH₂NH—. A more specific        embodiment does not encompass compounds disclosed in        international patent application WO 03/066624.    -   21) When E is meta-phenyl, substituted at the position para to        the —[CH₂]_(n)— moiety with OH, n is 1, and D is optionally        substituted ortho-phenyl, X is not —O—. In a specific        embodiment, when E is meta-(optionally substituted phenyl), n is        1, D is optionally substituted ortho-phenyl, and X is —O—, A is        not substituted tetrahydro-2H-pyran (i.e., tetrahydro-2H-pyran        substituted with at least one moiety in addition to X). A more        specific embodiment does not encompass compounds disclosed in        U.S. Pat. No. 6,951,840.    -   22) E is not optionally substituted quinazolin-4(3H)-one. In a        specific embodiment, when E is optionally substituted        quinazolin-4(3H)-one, n is 1, and D is phenyl, X is not —NH—. In        another embodiment, when E is optionally substituted        quinazolin-4(3H)-one, n is 1, D is phenyl, and X is —NH—, A is        not 4,5-dihydro-1H-imidazole. A more specific embodiment does        not encompass compounds disclosed in international patent        application WO 02/081467.    -   23) When E is para-phenyl, and n is 1, D is not optionally        substituted isoindoline-1,3-dione. In a specific embodiment,        when E is para-phenyl, n is 1, and D is optionally substituted        isoindoline-1,3-dione, X is not —OCH₂—. In another specific        embodiment, when E is para-phenyl, n is 1, D is        isoindoline-1,3-dione, X is —OCH₂—, and R₂ is H, A is not        phenyl. A more specific embodiment does not encompass compounds        disclosed in international patent application WO 02/028830.    -   24) D is not piperidine. In a specific embodiment, when E is        purine, n is 1, and D is piperidine, X is not a bond. In another        specific embodiment, when E is purine, n is 1, D is piperidine,        and X is a bond, A is not 1,2,3,4-tetrahydro-1,8-naphthyridine.        A more specific embodiment does not encompass compounds        disclosed in international patent application WO 02/018384.    -   25) When E is meta-(optionally substituted phenyl), n is 1, D is        optionally substituted phenyl, and X is O, A is not substituted        phenyl. In a specific embodiment, when E is meta-(optionally        substituted phenyl), n is 1, D is optionally substituted phenyl,        R₁ is acetyl, R₂ is ethyl, and X is O, A is not substituted        phenyl. A more specific embodiment does not encompass compounds        disclosed in international patent application WO 02/000245.    -   26) When E is para-phenyl, n is 1, and D is phenyl, X is not        —NH—, —CH₂NH—, or —NHCH₂—. In a specific embodiment, when E is        para-phenyl, n is 1, and D is meta-phenyl, X is not —NH—,        —CH₂NH—, or —NHCH₂—. In another specific embodiment, when E is        para-phenyl, n is 1, D is meta-phenyl, and R₂ is H, X is not        —NH—, —CH₂NH—, or —NHCH₂—. A more specific embodiment does not        encompass compounds disclosed in U.S. Pat. No. 6,677,360 or        international patent application WO 00/035864.    -   27) When E is optionally substituted phenyl, n is 1, D is        optionally substituted phenyl, and X is —O—, A is not optionally        substituted phenyl. In a specific embodiment, when E is        meta-(substituted phenyl), n is 1, D is meta-(substituted        phenyl), and X is —O—, A is not optionally substituted phenyl.        In another specific embodiment, when E is meta-(substituted        phenyl), n is 1, D is meta-(substituted phenyl), R₁ is H, R₂ is        H, and X is —O—, A is not optionally substituted phenyl. A more        specific embodiment does not encompass compounds disclosed in        international patent application WO 01/054486.    -   28) When E is para-phenyl, n is 1, and D is optionally        substituted imidazolidin-4-one (i.e., imidazolidin-4-one        optionally substituted with at least one moiety in addition to X        and A), X is not —CH₂—. In a specific embodiment, E is        para-phenyl, n is 1, D is optionally substituted        imidazolidin-4-one (i.e., imidazolidin-4-one optionally        substituted with at least one moiety in addition to X and A),        and X is —CH₂—, A is not pyridine. A more specific embodiment        does not encompass compounds disclosed in U.S. Pat. No.        6,903,128.    -   29) When E is para-(optionally substituted phenyl), n is 1, and        D is optionally substituted pyridin-2(1H)-one, X is not —CH₂—.        In a specific embodiment, when E is para-(optionally substituted        phenyl), n is 1, D is optionally substituted pyridin-2(1H)-one,        and X is —CH₂—, A is not phenyl. A more specific embodiment does        not encompass compounds disclosed in U.S. Pat. No. 6,916,933.    -   30) When E is para-phenyl, and n is 1, D is not        quinazoline-2,4(1H,3H)-dione or 2,4-dimethyleneimidazolidine. In        a specific embodiment, when E is para-phenyl, n is 1, and X is        —CH₂—, D is not quinazoline-2,4(1H,3H)-dione or        2,4-dimethyleneimidazolidine. A more specific embodiment does        not encompass compounds disclosed in U.S. Pat. No. 6,855,706.    -   31) A is not optionally substituted piperidine. In another        embodiment, when E is para-phenyl, and n is 1, D is not        ortho-phenyl. In a specific embodiment, when E is para-phenyl, n        is 1, and D is ortho-phenyl, X is not —CH₂—. In another specific        embodiment, when E is para-phenyl, n is 1, D is ortho-phenyl,        and X is —CH₂—, A is not optionally substituted piperidine. A        more specific embodiment does not encompass compounds disclosed        in U.S. Pat. No. 6,469,047.    -   32) When E is para-phenyl, and n is 1, D is not optionally        substituted phenyl. In a specific embodiment, when E is        para-phenyl, n is 1, and D is optionally substituted phenyl, X        is not —CH₂—, —O— or —OCH₂—. A more specific embodiment does not        encompass compounds disclosed in U.S. Pat. No. 6,420,418.    -   33) When E is para-phenyl, and n is 1, D is not optionally        substituted phenyl. In a specific embodiment, when E is        para-phenyl, n is 1, and D is optionally substituted phenyl, X        is not —CH₂—, —OCH₂—, —NH—, or —CH₂NH—. A more specific        embodiment does not encompass compounds disclosed in Japanese        patent 2001089368.    -   34) E is not optionally substituted pyrimidin-2(1H)-one (i.e.,        pyrimidin-2(1H)-one optionally substituted with at least one        moiety in addition to D and the —[CH₂]_(n)— moiety). In a        specific embodiment, when E is optionally substituted        pyrimidin-2(1H)-one, and n is 1, D is not piperidine or        piperazine. In another specific embodiment, when E is optionally        substituted pyrimidin-2(1H)-one, and n is 1, X is not —CH₂—,        —NH—, or —CH₂NH—. A more specific embodiment does not encompass        compounds disclosed in international patent application WO        00/061551.    -   35) D is not optionally substituted imidazolidin-4-one. In a        specific embodiment, when E is para-phenyl, and n is 1, D is not        optionally substituted imidazolidin-4-one. In another specific        embodiment, when E is para-phenyl, n is 1, and D is optionally        substituted imidazolidin-4-one, X is not —CH₂— or a bond. A more        specific embodiment does not encompass compounds disclosed in        U.S. Pat. Nos. 6,423,728; 6,806,365 or 6,229,011.    -   36) D is not optionally substituted phenyl. In a specific        embodiment, D is not phenyl or 2,6-dimethoxyphenyl (i.e., phenyl        substituted at the 2 and 6 positions by methoxy in addition to        its substitutions by E and X). In another specific embodiment,        when E is para-phenyl, and n is 1, D is not optionally        substituted phenyl. In another specific embodiment, when E is        para-phenyl, n is 1, and D is optionally substituted phenyl, X        is not —CH₂—, —OCH₂—, or —CH₂NH—. A more specific embodiment        does not encompass compounds disclosed in U.S. Pat. No.        6,855,843.    -   37) E is not optionally substituted indole. In a specific        embodiment, when E is optionally substituted indole, and n is 1,        D is not substituted tetrahydro-2H-pyran. A more specific        embodiment does not encompass compounds disclosed in U.S. Pat.        No. 6,610,502.    -   38) E is not optionally substituted isoxazole (i.e., isoxazole        optionally substituted with at least one moiety in addition to D        and —[CH₂]_(n)—). In a specific embodiment, when E is isoxazole,        and n is 1, D is not phenyl. In another specific embodiment,        when E is isoxazole, n is 1, and D is phenyl, X is not —OCH₂— or        —CH₂—. A more specific embodiment does not encompass compounds        disclosed in U.S. Pat. Nos. 6,114,328 or 5,849,736, or        international patent application WO 95/14683.    -   39) When E is phenyl, n is 1, and D is phenyl, X is not —OCH₂—.        In a specific embodiment, when E is phenyl, n is 1, D is phenyl,        and X is —OCH₂—, A is not phenyl. A more specific embodiment        does not encompass compounds disclosed in Japanese patent        09118662.    -   40) E is not optionally substituted imidazolidine-2,4-dione        (i.e., imidazolidine-2,4-dione optionally substituted with at        least one moiety in addition to D and —[CH₂]_(n)—). A is not        optionally substituted benzoimidazole (i.e., benzoimidazole        optionally substituted with at least one moiety in addition to        X). In a specific embodiment, when E is optionally substituted        imidazolidine-2,4-dione, n is not 2. In another specific        embodiment, when E is optionally substituted        imidazolidine-2,4-dione, and n is 2, D is not phenyl. In another        specific embodiment, when E is optionally substituted        imidazolidine-2,4-dione, n is 2, and D is phenyl, A is not        benzoimidazole. A more specific embodiment does not encompass        compounds disclosed in U.S. Pat. No. 6,620,820.    -   41) E is not optionally substituted morpholine. In a specific        embodiment, when E is optionally substituted morpholine, and n        is 1, D is not optionally substituted phenyl. In another        specific embodiment, when E is optionally substituted        morpholine, n is 1, and D is optionally substituted phenyl, X is        not —OCH₂—. A more specific embodiment does not encompass        compounds disclosed in U.S. Pat. No. 3,658,806.    -   42) When E is optionally substituted phenyl, and n is 1, D is        not optionally substituted phenyl. In a specific embodiment,        when E is optionally substituted phenyl, n is 1, and D is        optionally substituted phenyl, A is not optionally substituted        phenyl. In another specific embodiment, when E is optionally        substituted phenyl, n is 1, D is optionally substituted phenyl,        and X is —O—, A is not optionally substituted phenyl. A specific        embodiment does not encompass diisodityrosine. A more specific        embodiment does not encompass compounds disclosed in U.S. patent        application 2005/233964 or 2005/074838, or in international        patent application WO 05/076972, WO 05/069845, or WO 04/094590.    -   43) When E is phenyl, and n is 1, D is not optionally        substituted phenyl. In a specific embodiment, when E is phenyl,        n is 1, and D is optionally substituted phenyl, X is not —O—. In        another embodiment, when E is phenyl, A is not optionally        substituted phenyl. A more specific embodiment does not        encompass compounds disclosed in U.S. patent application        2005/059705.    -   44) When E is optionally substituted pyrimidin-2(1H)-one, and n        is 1, D is not piperidine or piperazine. In another embodiment,        when D is piperidine, and n is 1, X is not —NH— or —NHCH₂—. In        another embodiment, when D is piperazine, X is not —CH₂—. A more        specific embodiment does not encompass compounds disclosed in        U.S. patent application 2004/077638 or 2004/063934.    -   45) When E is optionally substituted phenyl, and n is 1, D is        not optionally substituted phenyl. In a specific embodiment,        when E is optionally substituted phenyl, n is 1, and D is        optionally substituted phenyl, A is not phenyl. In another        specific embodiment, when E is optionally substituted phenyl, n        is 1, and D is optionally substituted phenyl, X is not —OCH₂—. A        more specific embodiment does not encompass compounds disclosed        in Skaff, O., et al., JOC 70(18):7353-7363 (2005).    -   46) D is not optionally substituted indoline. In a specific        embodiment, when E is optionally substituted phenyl, and n is 1,        D is not optionally substituted indoline. In another specific        embodiment, when E is optionally substituted phenyl, n is 1, and        D is optionally substituted indoline, X is not a bond. A more        specific embodiment does not encompass compounds disclosed in        Nicolaou, K. C., et al., JACS 126(40):12897-12906 (2004) or        Nicolaou, K. C., et al., Angew. Chemie, Int. Ed.        42(15):1753-1758 (2003).    -   47) E is not optionally substituted triazole. In another        embodiment, D is not optionally substituted tetrahydro-2H-pyran.        In a specific embodiment, E is not triazole. In another specific        embodiment, when E is optionally substituted triazole, D is not        optionally substituted tetrahydro-2H-pyran. In another specific        embodiment, when E is optionally substituted triazole, A is not        phenyl. In another specific embodiment, when E is optionally        substituted triazole, X is not —O— or —OCH₂—. A more specific        embodiment does not encompass compounds disclosed in        Kuijpers, B. H. M., et al., Organic Let. 6(18):3123-3126 (2004).    -   48) E is not optionally substituted triazole or isoxazole. In        another embodiment, D is not optionally substituted        tetrahydro-2H-pyran. In a specific embodiment, when E is        triazole or isoxazole, and n is 1, D is not optionally        substituted tetrahydro-2H-pyran. In another specific embodiment,        when E is triazole or isoxazole, n is 1, and D is optionally        substituted tetrahydro-2H-pyran, X is not —OCH₂—. A more        specific embodiment does not encompass compounds disclosed in        Dondoni, A., et al., Organic Let. 6(17):2929-2932.    -   49) When E is optionally substituted phenyl, n is 1, and D is        optionally substituted phenyl, A is not phenyl. In a specific        embodiment, when E is optionally substituted phenyl, n is 1, D        is optionally substituted phenyl, and X is —OCH₂—, A is not        phenyl. A more specific embodiment does not encompass compounds        disclosed in Hutton, C. A. and Skaff, O., Tetrahedron Let.        44(26):4895-4898 (2003), and Yoburn, J. C. or Van Vranken, D.        L., Organic Let. 5(16):2817-2820 (2003).    -   50) When E is phenyl, n is 1, D is optionally substituted        phenyl, and X is —CH₂—, A is not pyrrolidine. A more specific        embodiment does not encompass compounds disclosed in Doherty, G.        A., et al., Bioorg. Med. Chem. Let. 13(11):1891-1895 (2003).    -   51) E is not optionally substituted pyrimidin-2(1H)-one or        5,6,7,8-tetrahydroquinazolin-2(3H)-one. In another embodiment, D        is not piperidine. In a specific embodiment, when E is        optionally substituted pyrimidin-2(1H)-one, and n is 1, D is not        piperidine. In another specific embodiment, when E is optionally        substituted pyrimidin-2(1H)-one, n is 1, and D is piperidine, X        is not —NH—, —CH₂—, or CH₂NH—. A more specific embodiment does        not encompass compounds disclosed in Zechel, C., et al., Bioorg.        Med. Chem. Let. 13(2):165-169 (2003).    -   52) A is not optionally substituted piperazine. In a specific        embodiment, when E is phenyl, n is 1, D is phenyl, and X is        —CH₂—, A is not optionally substituted piperazine. A more        specific embodiment does not encompass compounds disclosed in        Castanedo, G. M., et al., Bioorg. Med. Chem. Let.        12(20):2913-2917 (2002).    -   53) E is not optionally substituted indole. In a specific        embodiment, when E is optionally substituted indole, n is 1, and        D is optionally substituted tetrahydro-2H-pyran, X is not        —CH₂O—. In another specific embodiment, when E is optionally        substituted indole, n is 1, D is optionally substituted        tetrahydro-2H-pyran, and X is —CH₂O—, A is not phenyl. A more        specific embodiment does not encompass compounds disclosed in        Nishikawa, T., et al., Bioscience, Biotech. and Biochem.        66(10):2273-2278 (2002) or Nishikawa, T., et al., Org. Biomol.        Chem. 3(4):687-700 (2005).    -   54) E, D and A are not all phenyl. In a specific embodiment,        when E, D and A are all phenyl, X is not —CH₂—. A more specific        embodiment does not encompass compounds disclosed in Sircar, I.,        et al., Bioorg. Med. Chem. 10(6):2051-2066 (2002).    -   55) A is not cyclopropyl. In a specific embodiment, when E is        phenyl, n is 1, D is optionally substituted phenyl, and X is        —O—, A is not cyclopropyl. In another embodiment, D is not        2H-imidazol-2-one. In a specific embodiment, when E is phenyl, n        is 1, D is 2H-imidazol-2-one, and X is —CH₂—, A is not phenyl. A        more specific embodiment does not encompass compounds disclosed        in Yang, G. X., et al., Bioorg. Med. Chem. Let. 12(11):1497-1500        (2002).    -   56) E is not purine. In another embodiment, D is not piperidine.        In a specific embodiment, when E is purine, n is 1, D is        piperidine, and X is —CH₂NH—, A is not imidazole. A more        specific embodiment does not encompass compounds disclosed in        Peyman, A., et al., Angew. Chemie 39(16):2874-2877 (2000).    -   57) When E is optionally substituted phenyl, n is 1, and D is        optionally substituted phenyl, X is not —O—. In a specific        embodiment, when E is optionally substituted phenyl, n is 1, D        is optionally substituted phenyl, and X is —O—, A is not        optionally substituted phenyl. A more specific embodiment does        not encompass compounds disclosed in Wu, W., et al., J. Biol.        Chem. 274(36):25933-25944 (1999) or Jacob, J. S., et al., J.        Biol. Chem. 271(33):19950-19956 (1996).    -   58) E is not 4,5-dihydroisoxazole (i.e., 4,5-dihydroisoxazole        connected to D and the —[CH₂]_(n)— moiety). In a specific        embodiment, when E is 4,5-dihydroisoxazole, n is 1, and A is        phenyl, X is not —OCH₂—. In another specific embodiment, when E        is 4,5-dihydroisoxazole, n is 1, A is phenyl, and X is —OCH₂—, A        is not optionally substituted piperidine. A more specific        embodiment does not encompass compounds disclosed in Wityak, J.,        et al, J. Med. Chem. 40(1)50-60 (1997).    -   59) When E is imidazole, n is 1, and D is optionally substituted        phenyl, X is not —OCH₂—. In a specific embodiment, when E is        imidazole, n is 1, D is optionally substituted phenyl, and X is        —OCH₂—, A is not phenyl. A more specific embodiment does not        encompass compounds disclosed in Feldman, K. S., et al., JOC        61(19):6656-6665 (1996).    -   60) E is not optionally substituted        3,4-dihydro-2H-benzo[b][1,4]thiazine. In another embodiment, D        is not optionally substituted        3,4-dihydro-2H-benzo[b][1,4]thiazine. In another embodiment, A        is not optionally substituted        3,4-dihydro-2H-benzo[b][1,4]thiazine. In a specific embodiment,        E, D and A are not all optionally substituted        3,4-dihydro-2H-benzo[b][1,4]thiazine. A more specific embodiment        does not encompass compounds disclosed in Napolitano, A., et        al., JOC 61(2):598-604 (1996).    -   61) E is not dihydropyrimidine-2,4(1H,3H)-dione. In a specific        embodiment, when E is dihydropyrimidine-2,4(1H,3H)-dione, and n        is 2, D is not optionally substituted tetrahydrofuran. A more        specific embodiment does not encompass compounds disclosed in        Nawrot, B., et al., Nucleosides & Nucleotides 14(1&2):143-165        (1995).    -   62) E is not indoline. In a specific embodiment, when E is        indoline, n is 1, and D is optionally substituted phenyl, A is        not optionally substituted phenyl. In another specific        embodiment, when E is indoline, n is 1, D is optionally        substituted phenyl, and A is optionally substituted phenyl, X is        not —O—. A more specific embodiment does not encompass compounds        disclosed in Naruse, N., et al., J. Antibiotics 46(12):1812-1818        (1993).    -   63) When E, A and D are all optionally substituted phenyl, X is        not —O—. A more specific embodiment does not encompass compounds        disclosed in Fetterer, R. H., et al., J. Parasit. 79(2):160-166        (1993).    -   64) When E, A and D are all optionally substituted phenyl, X is        not —OCH₂—. A more specific embodiment does not encompass        compounds disclosed in Schmidt, U., et al., Synthesis 12:1248-54        (1992), Schmidt, U., et al., JACS, Chem. Comm. 13:951-953 (1992)        or Schmidt, U., et al., JACS. Chem. Comm. 5:275-277 (1991).    -   65) When E is quinazoline, and n is 1, D is not phenyl. In a        more specific embodiment, when E is quinazoline, n is 1, and D        is phenyl, X is not —NH—. A more specific embodiment does not        encompass compounds disclosed in Lawson, E. C., et al., Letters        Drug Design & Disc. 1(1):14-18 (2004).    -   66) When E is phenyl, n is 1, and D is optionally substituted        phenyl, X is not —CH₂—. In a more specific embodiment, when E is        phenyl, n is 1, D is optionally substituted phenyl, and X is        —CH₂—, A is not pyrrolidine. A more specific embodiment does not        encompass compounds disclosed in Doherty, G. A., et al., Bioorg.        Med. Chem. Let. 13(17):2937-2938 (2003).    -   67) D does not comprise boron. A more specific embodiment does        not encompass compounds disclosed in Shull, B. K., et al., J.        Pharm. Sci. 89(2):215-222 (2000).    -   68) When E is phenyl, and n is 1, D is not        2,5-dioxo-pyrrolidine. In a specific embodiment, when E is        phenyl, n is 1, and D is 2,5-dioxo-pyrrolidine, A is not phenyl.        A more specific embodiment does not encompass compounds        disclosed in Tilley, J. W., et al., Bioorg. Med. Chem. Let.        11(1):1-4 (2001).    -   69) D is not optionally substituted tetrahydro-2H-pyran. In a        specific embodiment, when A is phenyl, and n is 1, D is not        optionally substituted tetrahydro-2H-pyran. A more specific        embodiment does not encompass compounds disclosed in Manabe, S.        and Ito, Y., Tennen Yuki Kagobutsu Toronkai Koen Yoshishu        41:139-143 (1999).    -   70) E is not isoxazole. In a specific embodiment, when E is        isoxazole, n is 1, and D is phenyl, X is not —OCH₂—. A more        specific embodiment does not encompass compounds disclosed in        Wityak, G, et al., JMC 40(8):1292 (1997).    -   71) E, D and A are not all optionally substituted indole. A more        specific embodiment does not encompass compounds disclosed in        Humphries, K. A., et al., J. Electro. Chem. 346(1-2):377-403        (1993).    -   72) When E is substituted phenyl, n is 1, and D is substituted        phenyl, A is not phenyl. A more specific embodiment does not        encompass compounds disclosed in Schmidt, U., et al., Synthesis        10:1025-1030 (1992); Schmidt, U., et al., JACS Chem. Comm.        10:744 (1991); or Schmidt, U., et al., Angewandte Chemie        101(7):946-948 (1989).    -   73) When E is oxadiazole, and n is 1, D is not phenyl. In a        specific embodiment, when E is oxadiazole, n is 1, and D is        phenyl, A is not phenyl. A more specific embodiment does not        encompass compounds disclosed in Moussebois, C., et al., Helv.        Chimica Acta 60(1):237-242 (1977).    -   74) D is not 1H-imidazol-2(3H)-one. In a more specific        embodiment, when E is phenyl, n is 1, and A is phenyl, D is not        1H-imidazol-2(3H)-one.    -   75) A is not cyclopropyl. In a specific embodiment, when E is        phenyl, n is 1, and X is —O—, A is not cyclopropyl.    -   76) D is not optionally substituted purine. In a specific        embodiment, when E is phenyl, n is 1, and A is phenyl, D is not        purine.    -   77) When X is —CH₂—, A is not phenyl. In a specific embodiment,        when E is phenyl, n is 1, and X is —CH₂—, D is not optionally        substituted imidazole (e.g., 1H-imidazol-2(3H)-one).    -   78) D is not optionally substituted phthalazine. In a specific        embodiment, when E is phenyl, n is 1, and X is —CH₂—, D is not        optionally substituted phthalazine.    -   79) D is not optionally substituted 2-oxo-pyridine. In a        specific embodiment, when E is phenyl, n is 1, and X is —CH₂—, D        is not optionally substituted 2-oxo-pyridine.    -   80) A is not optionally substituted morpholine. In a specific        embodiment, when E is phenyl, n is 1, and X is —CH₂—, A is not        optionally substituted morpholine.    -   81) None of E, A or D is optionally substituted piperidine or        piperazine.    -   82) When E is imidazole, n is 1, and D is optionally substituted        triazole, X is not —NH—. In a specific embodiment, when E is        imidazole, n is 1, D is optionally substituted triazole, and X        is —NH—, A is not optionally substituted phenyl.

This invention encompasses stereomerically pure compounds andstereomerically enriched compositions of them. Stereoisomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns, chiral resolving agents, or enzymatic resolution. See,e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill,NY, 1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions, p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind., 1972).

Particular compounds of the invention are potent TPH1 inhibitors.Specific compounds have a TPH1_IC₅₀ of less than about 10, 5, 2.5, 1,0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 μM.

Particular compounds are selective TPH1 inhibitors. Specific compoundshave a TPH1_IC₅₀ that is about 10, 25, 50, 100, 250, 500, or 1000 timesless than their TPH2_IC₅₀.

Particular compounds do not significantly inhibit human tyrosinehydroxylase (TH). For example, specific compounds have an IC₅₀ for TH ofgreater than about 100, 250, 500 or 1000 μM.

Particular compounds do not significantly inhibit human phenylalaninehydroxylase (PAH). For example, specific compounds have an IC₅₀ for PAHof greater than about 100, 250, 500 or 1000 μM.

Particular compounds of the invention do not significantly bind (e.g.,inhibit with an IC₅₀ of greater than about 10, 25, 50, 100, 250, 500,750, or 1000 μM) to one or more of the following: angiotensin convertingenzyme, erythropoietin (EPO) receptor, factor IX, factor XI, integrin(e.g., α4), isoxazoline or isoxazole fibrinogen receptor,metalloprotease, neutral endopeptidase (NEP), phosphatase (e.g.,tyrosine phosphatase), phosphodiesterase (e.g., PDE-4), polymerase,PPARγ, TNF-α, vascular cell adhesion molecule-1 (VCAM-1), or thevitronectin receptor. The ability of a compound to bind to (e.g.,inhibit) any of these targets can be readily determined using methodsknown in the art, as described in references cited above. Specificcompounds of the invention do not inhibit cell adhesion.

When administered to mammals (e.g., mice, rats, dogs, monkeys orhumans), certain compounds of the invention do not readily cross theblood/brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or0.01 percent of compound in the blood passes into the brain). Theability or inability of a compound to cross the blood/brain barrier canbe determined by methods known in the art. See, e.g., Riant, P. et al.,Journal of Neurochemistry 51:421-425 (1988); Kastin, A. J., Akerstrom,V., J. Pharmacol. Exp. Therapeutics 294:633-636 (2000); W. A. Banks, W.A., et al., J. Pharmacol. Exp. Therapeutics 302:1062-1069 (2002).

5.3. Synthesis of Compounds

Compounds of the invention can be prepared by methods known in the art,and by methods described herein.

For example, with reference to formula I, compounds in which E is phenyland D is optionally substituted pyrazine, pyridiazine, pyridine orphenyl can generally be prepared by the method shown in Scheme 1:

wherein, for example:

Compounds wherein X is —OCR₃— can generally be prepared using the methodshown in Scheme 2, wherein R₃ is CF₃ and D is pyrimidine:

wherein, for example, A is optionally substituted phenyl, biphenyl ornapthyl.

Compounds of the invention can also be prepared using the approach shownbelow in Scheme 3:

wherein P₁ is R₁ or a protecting group; P₂ is a protecting group; P₃ isOR₂ or a protecting group; X′ is, for example, O or N; Y₁ and Y₃ arehalogen (e.g., Br, Cl) or an appropriate pseudohalide (e.g., triflate);and each R′ is independently hydrogen or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are takentogether with the oxygen atoms to which they are attached to provide acyclic dioxaborolane (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane).The groups A, R₁, R₂, R₃, R₆ and m are defined elsewhere herein. Themoieties Z″₁, Z″₂, Z″₃, and Z″₄ are also defined herein, although it isto be understood that with regard to the scheme shown above, one of themis attached to the phenyl ring. For example, Z″₁ and Z″₄ may beindependently CR₁₀ (which is defined herein), while Z″₂ is N and Z″₃ isa carbon atom bound to the adjacent phenyl ring.

The individual reactions shown above can be performed using conditionsknown in the art. For example, palladium catalysts and conditionssuitable for the Suzuki coupling of the boron and halogen-containingmoieties are well known, and examples are provided below. In addition,types and appropriate uses of protecting groups are well known, as aremethods of their removal and replacement with moieties such as, but notlimited to, hydrogen (e.g., hydrolysis under acidic or basicconditions).

The A moiety can be bicyclic (e.g., optionally substituted biphenyl). Insuch cases, the starting material containing A can be prepared as shownbelow:

wherein Y₂ is halogen or pseudohalogen, and each R is independentlyhydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle,aryl, or heterocycle, or are taken together with the oxygen atoms towhich they are attached to provide a cyclic dioxaborolane (e.g.,4,4,5,5-tetramethyl-1,3,2-dioxaborolane).

Another approach to the preparation of compounds wherein D is optionallysubstituted pyrimidine or triazine is shown below in Scheme 4:

wherein, for example, X is N, O or S, and FG is defined below:

FG=B(OH)₂ when E is optionally substituted Phenyl

FG=H when E is:

Ester derivatives of these and other compounds of the invention can bereadily prepared using methods such as that shown below in Scheme 5,wherein E is optionally substituted phenyl:

An alternate approach to the preparation of triazine-based compounds isshown below in Scheme 6:

The cyclic moiety D can be any of a variety of structures, which arereadily incorporated into compounds of the invention. For example,compounds wherein D is oxazole can be prepared as shown below in Scheme7:

Using methods known in the art, the synthetic approaches shown above arereadily modified to obtain a wide range of compounds. For example,chiral chromatography and other techniques known in the art may be usedto separate stereoisomers of the final product. See, e.g., Jacques, J.,et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); andWilen, S. H., Tables of Resolving A gents and Optical Resolutions, p.268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.,1972). In addition, as shown in some of the schemes above, syntheses mayutilize chiral starting materials to yield stereomerically enriched orpure products.

5.4. Methods of Use

This invention encompasses a method of inhibiting TPH, which comprisescontacting TPH with a compound of the invention (i.e., a compounddisclosed herein). In a particular method, the TPH is TPH1. In another,the TPH is TPH2. In a particular method, the inhibition is in vitro. Inanother, the inhibition is in vivo.

One embodiment encompasses a method of inhibiting TPH1 in a mammal,which comprises administering to the mammal a compound of the invention.In a particular method, TPH2 is not significantly inhibited. In onemethod, the compound does not readily cross the blood/brain barrier. Inanother, the compound is a selective inhibitor of TPH1.

This invention encompasses methods of treating, preventing and managingvarious diseases and disorders mediated by peripheral serotonin, whichcomprise inhibiting TPH1 activity in a patient in need of suchtreatment, prevention or management. In a particular embodiment, theinhibition is accomplished by administering to the patient atherapeutically or prophylactically effective amount of a potent TPH1inhibitor. Examples of potent TPH1 inhibitors are disclosed herein.

Particular diseases and disorders include carcinoid syndrome andgastrointestinal diseases and disorders. Examples of specific diseasesand disorders include abdominal pain (e.g., associated with medullarycarcinoma of the thyroid), anxiety, carcinoid syndrome, celiac disease,constipation (e.g., constipation having an iatrogenic cause, andidiopathic constipation), Crohn's disease, depression, diabetes,diarrhea (e.g., bile acid diarrhea, enterotoxin-induced secretorydiarrhea, diarrhea having an iatrogenic cause, idiopathic diarrhea(e.g., idiopathic secretory diarrhea), and traveler's diarrhea), emesis,functional abdominal pain, functional dyspepsia, irritable bowelsyndrome (IBS), lactose intolerance, MEN types I and II, Ogilvie'ssyndrome, Pancreatic Cholera Syndrome, pancreatic insufficiency,pheochromacytoma, scleroderma, somatization disorder, andZollinger-Ellison Syndrome.

In particular methods of the invention, the treatment, management and/orprevention of a disease or disorder is achieved while avoiding adverseeffects associated with alteration of central nervous system (CNS)serotonin levels. Examples of such adverse effects include agitation,anxiety disorders, depression, and sleep disorders (e.g., insomnia andsleep disturbance).

5.5. Pharmaceutical Compositions

This invention encompasses pharmaceutical compositions comprising one ormore compounds of the invention. Certain pharmaceutical compositions aresingle unit dosage forms suitable for oral, mucosal (e.g., nasal,sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous,intravenous, bolus injection, intramuscular, or intraarterial), ortransdermal administration to a patient. Examples of dosage formsinclude, but are not limited to: tablets; caplets; capsules, such assoft elastic gelatin capsules; cachets; troches; lozenges; dispersions;suppositories; ointments; cataplasms (poultices); pastes; powders;dressings; creams; plasters; solutions; patches; aerosols (e.g., nasalsprays or inhalers); gels; liquid dosage forms suitable for oral ormucosal administration to a patient, including suspensions (e.g.,aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or awater-in-oil liquid emulsions), solutions, and elixirs; liquid dosageforms suitable for parenteral administration to a patient; and sterilesolids (e.g., crystalline or amorphous solids) that can be reconstitutedto provide liquid dosage forms suitable for parenteral administration toa patient.

The formulation should suit the mode of administration. For example, theoral administration of a compound susceptible to degradation in thestomach may be achieved using an enteric coating. Similarly, aformulation may contain ingredients that facilitate delivery of theactive ingredient(s) to the site of action. For example, compounds maybe administered in liposomal formulations in order to protect them fromdegradative enzymes, facilitate transport in circulatory system, andeffect their delivery across cell membranes.

Similarly, poorly soluble compounds may be incorporated into liquiddosage forms (and dosage forms suitable for reconstitution) with the aidof solubilizing agents, emulsifiers and surfactants such as, but notlimited to, cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin,Captisol®, and Encapsin™ (see, e.g., Davis and Brewster, Nat. Rev. DrugDisc. 3:1023-1034 (2004)), Labrasol®, Labrafil®, Labrafac®, cremafor,and non-aqueous solvents, such as, but not limited to, ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, dimethyl sulfoxide (DMSO), biocompatible oils (e.g.,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acidesters of sorbitan, and mixtures thereof (e.g., DMSO:cornoil).

Poorly soluble compounds may also be incorporated into suspensions usingother techniques known in the art. For example, nanoparticles of acompound may be suspended in a liquid to provide a nanosuspension (see,e.g., Rabinow, Nature Rev. Drug Disc. 3:785-796 (2004)). Nanoparticleforms of compounds described herein may be prepared by the methodsdescribed in U.S. Patent Publication Nos. 2004-0164194, 2004-0195413,2004-0251332, 2005-0042177 A1, 2005-0031691 A1, and U.S. Pat. Nos.5,145,684, 5,510,118, 5,518,187, 5,534,270, 5,543,133, 5,662,883,5,665,331, 5,718,388, 5,718,919, 5,834,025, 5,862,999, 6,431,478,6,742,734, 6,745,962, the entireties of each of which are incorporatedherein by reference. In one embodiment, the nanoparticle form comprisesparticles having an average particle size of less than about 2000 nm,less than about 1000 nm, or less than about 500 nm.

The composition, shape, and type of a dosage form will typically varydepending with use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Howto account for such differences will be apparent to those skilled in theart. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1996).

5.5.1. Oral Dosage Forms

Pharmaceutical compositions of the invention suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms are prepared by combining the activeingredient(s) in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms. If desired, tablets can becoated by standard aqueous or non-aqueous techniques. Such dosage formscan be prepared by conventional methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary. Disintegrants may beincorporated in solid dosage forms to facility rapid dissolution.Lubricants may also be incorporated to facilitate the manufacture ofdosage forms (e.g., tablets).

5.5.2. Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including subcutaneous, intravenous (including bolus injection),intramuscular, and intraarterial. Because their administration typicallybypasses patients' natural defenses against contaminants, parenteraldosage forms are specifically sterile or capable of being sterilizedprior to administration to a patient. Examples of parenteral dosageforms include solutions ready for injection, dry products ready to bedissolved or suspended in a pharmaceutically acceptable vehicle forinjection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude: Water for Injection USP; aqueous vehicles such as SodiumChloride Injection, Ringer's Injection, Dextrose Injection, Dextrose andSodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as corn oil,cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropylmyristate, and benzyl benzoate.

6. EXAMPLES 6.1. Production of tph1 Gene Disrupted Mice

Exon 3 of the murine TPH1 gene was removed by gene targeting essentiallyas described by Wattler et al., Biotechniques 26(6):1150-6 (1999). Theresulting knockout animals displayed normal TPH activity in the brainbut drastically reduced TPH expression in the gut.

6.2. Physiological Effects of tph1 Gene Disruption

Mice homozygous (−/−) for the disruption of tph1 were studied inconjunction with mice heterozygous (+/−) for the disruption of the gene,along with wild-type (+/+) litter mates. During this analysis, the micewere subject to a medical work-up using an integrated suite of medicaldiagnostic procedures designed to assess the function of the major organsystems in a mammalian subject. By studying the homozygous (−/−)knockout mice in the described numbers and in conjunction withheterozygous(+/−) and wild-type (+/+) litter mates, more reliable andrepeatable data was obtained.

Disruption of tph1 gene primarily affected the GI tract isoform of TPH(TPH1), and had little or no effect on the brain isoform of TPH (TPH2).Disruption of the gene caused no measurable adverse effects on thecentral nervous system. This was confirmed by serotonin immunochemistry,which showed that serotonin was greatly reduced or absent in thestomach, duodenum, jejunum, ileum, cecum and colon, while serotoninlevels were unaffected in raphe neurons.

Mice homozygous (−/−) for the disruption of the tph1 gene had a decreasein thrombosis without a significant increase in bleeding or otheradverse indications.

6.3. HPLC Characterization

In some of the following synthetic examples, high performance liquidchromatography (HPLC) retention times are provided. Unless otherwisenoted, the various conditions used to obtain those retention times aredescribed below:

Method A: YMC-PACK ODS-A 3.0×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 4min.; flow rate=2 ml/min; observation wavelength=220 nm.

Method B: YMC-PACK ODS-A 3.0×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; % B from 10 to 100% over 4min.; flow rate=3 ml/min; observation wavelength=220 nm.

Method C: YMC-PACK ODS-A 3.0×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 5min.; flow rate=2 ml/min.; observation wavelength=220 nm.

Method D: Shim VP ODS 4.6×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 4min.; flow rate=3 mmin.; observation wavelength=220 nm.

Method E: Shim VP ODS 4.6×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 4min.; flow rate=3 mmin; observation wavelength=254 nm.

Method F: YMC-PACK ODS-A 4.6×33 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 4min.; flow rate=3 ml/min.; observation wavelength=220 nm.

Method G: YMC-PACK ODS-A 4.6×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 2min.; flow rate=2.5 ml/min.; observation wavelength=220 nm.

Method H: C18 4.6×20 mm; Solvent A=90% water, 10% MeOH, 0.1% TFA;Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 2 min.flow rate=2 ml/min.; observation wavelength=220 nm.

Method I: YMC PACK ODS-A 3.0×50 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 10 to 100% over 4min.; flow rate=2 ml/min.; observation wavelength=220 nm.

Method J: YMC Pack ODS-A 3.0×50 mm; Solvent A=H₂O, 0.1% TFA; SolventB=MeOH, 0.1% TFA; % B from about 10 to about 90% over 4 min.; flowrate=2 ml/min.; observation wavelength=220 nm.

Method K: Sunfire C18 50 mm×4.6 mm×3.5 μm; Solvent A=10 mM NH₄OAc inwater; Solvent B=MeCN; B % from 10 to 95% over 2 min.; flow rate=4.5ml/min.; observation wavelength=220 nm.

Method L: Sunfire C18 50 mm×4.6 mm×3.5 μm; Solvent A=10 mM NH₄OAc;Solvent B=MeCN; B % from 2 to 20% over 0.8 min, then to 95% B over 2min; flow rate=4.5 ml/min.; observation wavelength=220 nm.

Method M: YMC-PACK ODS-A 4.6×33 mm; Solvent A=90% water, 10% MeOH, 0.1%TFA; Solvent B=90% MeOH, 10% water, 0.1% TFA; B % from 0 to 100% over 5min.; flow rate=2.5 ml/min.; observation wavelength=254 nm.

Method N: YMC-PACK ODS-A 3.0×50 mm; Solvent A=H₂O, 0.1% TFA; SolventB=MeOH, 0.1% TFA; B % from 10 to 90% over 4 min.; flow rate=2 ml/min.;observation wavelength=220 and 254 nm.

Method O: YMC-PACK ODS-A 3.0×50 mm; Solvent A=90% water, 10% MeOH with0.1% TFA; Solvent B=90% MeOH, 10% water with 0.1% TFA; B % from 0 to100% over 4 min.; flow, rate=2 ml/min.; observation wavelength=220 and254 nm.

Method P: ShimPack VP ODS 4.6×50 mm; Solvent A=90% H₂O, 10% MeOH, 1%TFA; Solvent B=10% H₂O, 90% MeOH, 1% TFA; B % from 0 to 100% over 2min.; flow rate=3.5 ml/min.; observation wavelength=220 and 254 nm.

Method Q: Shim VP ODS 4.6×50 mm; Solvent A=H₂O with 0.1% TFA; SolventB=MeOH with 0.1% TFA; B % from 0 to 100% over 4 min.; flow rate=3ml/min.; observation wavelength=254 nm.

Method R: YMC Pack ODS-A 4.6×33 mm; Solvent A=H₂O, 0.1% TFA; SolventB=MeOH with 0.1% TFA; B % from 10 to 90% over 3 min.; flow rate 2ml/min.; observation wavelength 220 and 254 nm.

Method S: YMC-Pack ODS-A 3.0×50 mm; Solvent A=90% H₂O, 10% MeOH, 1% TFA;Solvent B=10% H₂O, 90% MeOH, 1% TFA; B % from 10 to 90% over 4 min.;flow rate=2 ml/min. observation wavelength=220 and 254 nm.

6.4. Synthesis of(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

A mixture of 2-amino-4,6-dichloro-[1,3,5]triazine (200 mg, 1.21 mmol),(R)-(+)-1-(2-naphthyl)ethylamine (207 mg, 1.21 mmol) anddiisopropyl-ethylamine (3.63 mmol) was dissolved in 150 ml of1,4-dioxane. The solution was refluxed at 90° C. for 3 hours. After thecompletion of reaction (monitored by LCMS), solvent was removed and thereaction mixture was extracted with CH₂Cl₂ (100 ml) and H₂O (100 ml).The organic layer was separated and washed with H₂O (2×100 ml), driedover Na₂SO₄, and concentrated in vacuo to give crude intermediate. Thecrude compound was dissolved in 5 ml of MeCN and 5 ml of H₂O in a 20 mlmicrowave reaction vial. To this solution were addedL-p-borono-phenylalanine (253 mg, 1.21 mmol), sodium carbonate (256 mg,2.42 mmol) and catalytic amount ofdichlorobis(triphenylphosphine)-palladium(II) (42.1 mg, 0.06 mmol). Themixture was sealed and stirred in the microwave reactor at 150° C. for 5minutes, followed by the filtration through celite. The filtrate wasconcentrated and dissolved in MeOH and H₂O (1:1) and purified bypreparative HPLC using MeOH/H₂O/TFA solvent system. The combined purefractions were evaporated in vacuo and further dried on a lyophilizer togive 238 mg of2-amino-3-{4-[4-amino-6-(1-naphthalen-2-yl)-ethylamino)-[1,3,5]triazin-2-yl]-phenyl}-propionicacid (yield: 46%, LC: Column: YMC Pack ODS-A 3.0×50 mm, % B=0˜100%,Gradient time=4 min, Flow Rate=2 ml/min, wavelength=220, Solvent A=90:10water:MeOH w/0.1% TFA, Solvent B=90:10 MeOH:water w/0.1% TFA, RT=2.785min, MS: M+1=429). NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.65 (d, 3H),3.22-3.42 (m, 2H), 4.3 (m, 1H), 5.45 (m, 1H), 7.4 (m, 1H), 7.6 (m 4H),7.8 (m, 4H), 8.2 (m, 2H).

6.5. Alternative Synthesis of(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

(R)-1-(1-(Napthalen-2-yl)ethyl)cyanoguanidine was prepared by forming amixture of naphthalene amine (1 equivalent), sodium dicyanide (0.95 eq.)and followed by 5N HCl (1 eq.) in n-BuOH:H₂O (1:1). The mixture wasrefluxed for 1 day in a sealed tube at 160° C., and progress of reactionwas monitored by LCMS. After completion of reaction, solvent (n-BuOH)was removed under reduced pressure and 1N HCl was added to adjust pH to3-5 range. The aqueous solution was extracted with EtOAc (2×100) andcombined organic phase was dried over Na₂SO₄. Solvent was removed invacuo to give crude product. The compound was purified by ISCO columnchromatography using as the solvent system EtOAc:hexane (7:3 and 1:1),to obtain white solid 48-71% yield for 1 g to 22.5 gram scale.

NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.5 (d, 3H), 5.1 (m, 1H), 7.5 (m, 4H),7.8 (s, 1H), 7.9 (m, 2H); LCMS: RT 1.69, M+1: 239, Yield: 71%.

The title compound was prepared from(R)-1-(1-(napthalen-2-yl)ethyl)cyanoguanidine according to the methodshown in Scheme 6.

6.6. Synthesis of(S)-2-Amino-3-(4-(4-amino-6-((4′-methylbiphenyl-4-yl)methylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

A mixture of 2-amino-4,6-dichloro-[1,3,5]triazine (100 mg, 0.606 mmol),4′-methyl-biphenyl-4-yl-methylamine (142 mg, 0.606 mmol), and cesiumcarbonate (394 mg, 1.21 mmol) was dissolved in 1,4-dioxane (1.5 ml) andH₂O (1.5 ml) in a 5 ml microwave vial. The mixture was stirred inmicrowave reactor at 100° C. for 15 minutes. Solvent was removed and theresidue was dissolved in CH₂Cl₂ (20 ml) and washed with H₂O (2×20 ml),dried over Na₂SO₄ and then removed in vacuo. The crude intermediate wasthen dissolved in 1.5 ml of MeCN and 1.5 ml of H₂O in a 5 ml microwavevial. To this solution were added L-p-borono-phenylalanine (126 mg,0.606 mmol), sodium carbonate (128 mg, 1.21 mmol) and catalytic amountof dichlorobis(triphenylphosphine)-palladium(II) (21.1 mg, 0.03 mmol).The mixture was sealed and stirred in the microwave reactor at 150° C.for 5 minutes followed by the filtration through celite. The filtratewas concentrated and dissolved in MeOH and H₂O (1:1) and purified bypreparative HPLC using MeOH/H₂O/TFA solvent system. The combined purefractions were evaporated in vacuo and further dried on a lyophilizer togive 21.6 mg of2-amino-3-(4-{4-amino-6-[(4′-methyl-biphenyl-4-ylmethyl)-amino]-[1,3,5]triazin-2-yl}-phenyl)-propionicacid (LC: Column: YMC Pack ODS-A 3.0×50 mm, % B=0˜100%, Gradient time=4min, Flow Rate=2 ml/min, wavelength=220, Solvent A=90:10 water:MeOHw/0.1% TFA, Solvent B=90:10 MeOH:water w/0.1% TFA, RT=3.096 min, MS:M+1=455). ¹H NMR (400 MHz, CD₃OD) δ 2.33 (s, 3H), 3.24-3.44 (m, 2H),4.38 (m, 1H), 7.02 (d, 2H), 7.42 (m, 2H), 7.50-7.60 (m, 6H), 8.22 (m,2H).

6.7. Synthesis of(S)-2-Amino-3-(4-(4-morpholino-6-(naphthalen-2-ylmethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

A mixture of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (121 mg,0.516 mmol), C-naphthalen-2-yl-methylamine hydrochloride (100 mg, 0.516mmol), cesium carbonate (336 mg, 1.03 mmol) was dissolved in 1,4-Dioxane(1.5 ml) and H₂O (1.5 ml) in a 5 ml microwave vial. The mixture wasstirred in microwave reactor at 180° C. for 600 seconds. Solvent wasremoved, and the residue was dissolved in CH₂Cl₂ (10 ml) and washed withH₂O (2×10 ml), dried over Na₂SO₄ and then in vacuo. The residue waspurified by preparative HPLC to give 20 mg intermediate (yield 11%,M+1=356). The intermediate was then dissolved in 0.5 ml of MeCN and 0.5ml of H₂O in a 2 ml microwave vial. To this solution were addedL-p-borono-phenylalanine (11.7 mg, 0.0562 mmol), sodium carbonate (11.9mg, 0.112 mmol) and a catalytic amount ofdichlorobis(triphenylphosphine)-palladium(II) (2.0 mg, 5%). The mixturewas sealed and stirred in the microwave reactor at 150° C. for 5 minutesfollowed by the filtration through celite. The filtrate was concentratedand dissolved in MeOH and H₂O (1:1) and purified by preparative HPLCusing MeOH/H₂O/TFA solvent system. The combined pure fractions wereevaporated in vacuo and further dried on lyophilizer to give 17 mg of2-amino-3-(4-{4-morpholin-4-yl-6-[(naphthalene-2-ylmethyl)-amino]-[1,3,5]triazin-2-yl}-phenyl)-propionicacid (yield: 63%, LC: Method B, RT=3.108 min, MS: M+1=486).

6.8. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(trifluoromethyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid

Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran)was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74 g, 10mmol) and trifluoromethyltrimethylsilane (TMSCF₃) (1.8 ml, 12 mmol) in10 ml THF at 0° C. The formed mixture was warmed up to room temperatureand stirred for 4 hours. The reaction mixture was then treated with 12ml of 1N HCl and stirred overnight. The product was extracted with ethylacetate (3×20 ml). The organic layer was separated and dried over sodiumsulfate. The organic solvent was evaporated to give 2.2 g of1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol, yield 90%.

NaH (80 mg, 60%, 3.0 mmol) was added to a solution of1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol (244 mg, 1 mmol) in10 ml of anhydrous THF. The mixture was stirred for 20 minutes,2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then thereaction mixture was heated at 70° C. for 1 hour. After cooling, 5 mlwater was added and ethyl acetate (20 ml) was used to extract theproduct. The organic layer was dried over sodium sulfate. The solventwas removed by rotovap to give 267 mg of4-chloro-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-2-ylamine,yield 71%.

In a microwave vial,4-chloro-2-amino-6-[1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine(33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 mlof acetonitrile, 0.7 ml of water. 0.3 ml of 1N aqueous sodium carbonatewas added to above solution followed by 5 mole percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated at 150° C. for 5 minutes with microwave irradiation.After cooling, the reaction mixture was evaporated to dryness. Theresidue was dissolved in 2.5 ml of methanol, and then was purified byPrep-LC to give 5.6 mg of2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionicacid. ¹H NMR (400 MHz, CD₃OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, 1H),7.74 (t, J=7.91 Hz 1H), 7.63 (t, J=8.06 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H),7.21 (m, 1H), 6.69 (s, 1H), 3.87 (m, 1H), 3.34 (m, 1H), 3.08 (m, 1H).

6.9. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-p-tolylethoxy)pyrimidin-4-yl)phenyl)propanoicacid

Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran)was added to a solution of 4-methyl-benzaldehyde (1.2 g, 10 mmol) andTMSCF₃ (1.8 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture waswarmed up to room temperature and stirred for 4 hours. The reactionmixture was then treated with 12 ml of 1N HCl and stirred overnight. Theproduct was extracted with ethyl acetate (3×20 ml). The organic layerwas separated and dried over sodium sulfate. The organic solvent wasevaporated to give 1.6 g of 1-(4-methylphenyl)-2,2,2-trifluoro-ethanol,yield 86%.

NaH (80 mg, 60%, 3.0 mmol) was added to a solution of1-(4-methylphenyl)-2,2,2-trifluoro-ethanol (190 mg, 1 mmol) in 10 ml ofanhydrous THF. The mixture was stirred for 20 minutes,2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then thereaction mixture was heated at 70° C. for 1 hour. After cooling, 5 mlwater was added and ethyl acetate (20 ml) was used to extract theproduct. The organic layer was dried over sodium sulfate. The solventwas removed by rotovap to give 209 mg of4-chloro-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine,yield 66%.

A microwave vial was charged with4-chloro-2-amino-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine(33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 mlof acetonitrile, 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1N)was added to above solution followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes with microwave. Aftercooling, the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, was then purified by Prep-LC to give14.6 mg of2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-methylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionicacid. ¹H NMR (300 MHz, CD₃OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24Hz, 4H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, 1H), 6.75 (m, 1H), 4.30 (t,1H), 3.21-3.44 (m, 2H), 2.37 (s, 3H).

6.10. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(1-cyclohexyl-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid

Cyclohexanecarbaldehyde (0.9 g, 5 mmol) was dissolved in 10 ml aqueous1,4-dioxane, to which 200 mg (10 mmol) sodium borohydride was added. Thereaction was run overnight at room temperature. After completion of thereaction, 5 ml 10% HCl solution was added and the product was extractedwith ethyl acetate. The organic layer was separated and dried oversodium sulfate. The organic solvent was evaporated to give 0.8 g of1-cyclohexyl-2,2,2-trifluoro-ethanol, yield 88%.

NaH (80 mg, 60%, 3.0 mmol) was added to the solution of1-cyclohexyl-2,2,2-trifluoro-ethanol (182 mg, 1 mmol) in 10 ml ofanhydrous THF, the mixture was stirred for 20 minutes,2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then thereaction mixture was heated at 70° C. for 1 hour. After cooling, 5 mlwater was added and ethyl acetate (20 ml) was used to extract theproduct. The organic layer was dried over sodium sulfate. The solventwas removed by rotovap to give 202 mg of4-chloro-6-[1-cyclohexyl-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine,yield 65%.

In a microwave vial,4-chloro-2-amino-6-[1-cyclohexane-2,2,2-trifluoro-ethoxy]-pyrimidine (33mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml ofacetonitrile, 0.7 ml of water, 0.3 ml of aqueous sodium carbonate (1M)was added to above solution followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes with a microwave. Aftercooling, the reaction mixture was evaporated to dryness, the residue wasdissolved in 2.5 ml of methanol, and the product was purified by Prep-LCto give 4.9 mg2-amino-3-{4-[2-amino-6-(1-cyclohexyl-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-propionicacid. ¹H NMR (300 MHz, CD₃Cl) δ 7.95 (d, J=8.39 Hz, 2H), 7.49 (d, J=8.39Hz, 2H), 6.72 (s, 1H), 5.90 (m, 1H), 4.33 (t, 1H), 3.21-3.44 (m, 2H),1.73-2.00 (m, 6H), 1.23-1.39 (m, 5H).

6.11. Synthesis of(S)-2-Amino-3-(4-(6-(2-fluorophenoxy)pyrimidin-4-yl)phenyl)propanoicacid

NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 2-fluorophenol(112 mg, 1 mmol) in 10 ml of anhydrous THF, the mixture was stirred for20 minutes, 4,6-dichloro-pyrimidine (149 mg, 1 mmol) was added and thenthe reaction mixture was heated at 70° C. for 1 hour. After cooling, 5ml water was added and ethyl acetate (20 ml) was used to extract theproduct. The organic layer was dried over sodium sulfate. The solventwas removed by rotovap to give 146 mg of4-chloro-6-(2-fluorophenoxy)-pyrimidine, yield 65%.

A microwave vial (2 ml) was charged with4-chloro-6-[2-fluorophenoxy]-pyrimidine, (33 mg, 0.1 mmol),4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of actonitrile, 0.7ml of water, 0.3 ml of aqueous sodium carbonate (1M) was added to abovesolution followed by 5 mol % ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness, the residue wasdissolved in 2.5 ml of methanol, and the product was purified withPrep-LC to give 4.9 mg2-amino-3-{4-[2-amino-6-(1-2-fluorophenyl-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-propionicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.74 (s, 1H), 8.17 (d, J=8.06 Hz, 2H),7.63 (s, 1H), 7.50 (d, J=8.06 Hz, 2H), 7.30 (m, 5H), 4.33 (m, 1H), 3.34(m, 1H).

6.12. Synthesis of(2S)-2-Amino-3-(4-(4-(3-(4-chlorophenyl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)propanoicacid

3-(4-Chlorophenyl)piperidine (232 mg, 1 mmol) was added to a solution of2,4-dichlorotriazine (149.97 mg, 1 mmol), and 300 mg diisopropylethylamine in 10 ml THF at 0° C. The formed mixture was warmed up to roomtemperature and stirred for 1 hour. The product was extracted with ethylacetate (3×20 ml). The organic layer was separated and dried over sodiumsulfate. The organic solvent was evaporated to give 328 mg of2-chloro-4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazine.

A microwave vial was charged with2-chloro-4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazine (62 mg,0.2 mmol), 4-borono-L-phenylalanine (60 mg, 0.3 mmol), 1 ml ofacetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.6 ml; 1M)was added to the solution, followed by 5 mol percentdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes with microwave. Aftercooling, the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, was then purified by Prep-LC to give5.1 mg of2-amino-3-(4-{4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazin-2-yl}-phenyl)-propionicacid. ¹H NMR (400 MHz, CD₃Cl) δ 8.58 (d, 2H), 8.05 (d, 2H), 7.47 (m,5H), 4.96 (m, 1H), 4.23 (m, 2H), 3.21-3.44 (m, 4H), 2.37 (m, 5H).

6.13. Synthesis of(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-phenylethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid

NaH (80 mg, 60%, 3.0 mmol) was added to a solution of2,2,2-trifluoro-1-phenyl-ethanol (176 mg, 1 mmol) in 10 ml of anhydrous1,4-dioxane. The mixture was stirred for 20 minutes, then added to asolution of 2-amino-4,6-dichloro-triazine (164 mg, 1 mmol) in 30 ml of1,4-dioxane at 0° C. for 1 hour. The reaction mixture was then warmed toroom temperature. After completion of the reaction, 5 ml of water wasadded and ethyl acetate (20 ml) was used to extract the product. Theorganic layer was dried over sodium sulfate. The solvent was removed byrotovap to give 198 mg of4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine,yield 65%.

A microwave vial was charged with4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine(33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml ofactonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M)was added to above solution followed by 5 mol percentdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, was then purified with Prep-LC to give3.2 mg2-amino-3-{4-[4-amino-6-(1-phenyl-2,2,2-trifluoro-ethoxy]-[1,3,5]triazin-2-yl]-phenyl)-propionicacid. ¹H NMR (300 MHz, CD₃OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2H),7.33 (m, 5H) 6.62 (m, 1H), 4.19 (t, 1H), 3.1-3.33 (m, 2H).

6.14. Synthesis of(S)-2-Amino-3-(5-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)pyridin-2-yl)propanoicacid

A microwave vial was charged with6-chloro-N-[1-naphthalen-2-yl-ethyl]-[1,3,5]triazine-2,4-diamine (30 mg,0.1 mmol), 2-bocprotected-amino-3-{5-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl-]-propionicacid (50 mg, 0.15 mmol) 1 ml of acetonitrile, and 0.7 ml of water.Aqueous sodium carbonate (0.3 ml; 1N) was added to the solution,followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II).The reaction vessel was sealed and heated to 150° C. for 5 minutes bymicrowave. After cooling, the reaction mixture was evaporated todryness. The residue was dissolved in 2.5 ml of methanol, and was thenpurified by Prep-LC to give 7 mg of boc protected2-amino-3-{5-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2-yl]-pyridin-2-yl}proionicacid.

The above product (7.0 mg) was dissolved in 0.1 ml of 10% TFA/DCMsolution for 2 hours to provide 1.1 mg of2-amino-3-{3-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2-yl]-pyridin-2-yl}proionicacid. ¹H NMR (300 MHz, CD₃Cl) δ 9.35 (d, 1H), 8.57 (m, 1H), 7.85 (m,4H), 7.45 (m, 4H), 6.94 (s, 1H), 5.58 (m, 1H), 4.72 (m, 2H), 4.44 (m,1H), 1.42 (d, 3H).

6.15. Synthesis of(S)-2-Amino-3-(3-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)propanoicacid

6-Chloro-N-[1-naphthalen-2-yl-ethyl]-[1,3,5]triazine-2,4-diamine (30 mg,0.1 mmol), 2-boc-protectedamino-3-{3-[4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionicacid (50 mg, 0.15 mmol), 1 ml of acetonitrile, and 0.7 ml of water.Aqueous sodium carbonate (0.3 ml and 1N) was added to a microwave vial,followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes with microwave. Aftercooling, the reaction mixture was evaporated to dryness, the residue wasdissolved in 2.5 ml of methanol, and then was purified with Prep-LC togive 6.8 mg of boc protected2-amino-3-{3-[4-amino-6-(1-naphthalen-2-yl-ethylamino)[1,3,5]triazin-2-yl]-pyrazol-1-yl}proionicacid.

The above product (6.8 mg) was stirred in 0.1 ml 10% TFA/DCM solutionfor 2 hours to provide 3 mg of2-amino-3-{3-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2-yl]-pyrazol-1-yl}proionicacid. ¹H NMR (300 MHz, CD₃Cl) δ 8.52 (s, 1H), 8.21 (s, 1H), 7.74 (m,4H), 7.36 (m, 3H), 5.35 (m, 1H), 4.72 (m, 2H), 4.44 (m, 1H), 1.55 (d,3H).

6.16. Synthesis of(S)-2-Amino-3-(4′-(3-(cyclopentyloxy)-4-methoxybenzylamino)biphenyl-4-yl)propanoicacid

Sodium triacetoxyl-borohydride (470 mg, 2.21 mmol) was added to asolution of 4-bromo-phenylamine (252 mg, 1.47 mmol) and3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mmol) in 10 ml of1,2-dicloroethtane (DCE), 0.5 ml of HOAc was added. The mixture wasstirred overnight at room temperature, followed by addition of 15 ml ofDCE. The organic phase was washed with water and dried over sodiumsulfate. The solvent was removed by rotovap to give 656 mg of crude(4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. It was usedfor next step without further purification.

An Emrys process vial (2-5 ml) for microwave was charged with(4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (84 mg, 0.22mmol), 4-borono-L-phenylalanine (46 mg, 0.22 mmol) and 2 ml ofacetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to abovesolution, followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol and purified with Prep-LC to give 5 mgof2-amino-3-[4′-(3-cyclophentyloxy-4-methoxy-benzylamino)-biphenyl-4-yl]-propionicacid, yield 5%. ¹H-NMR (400 MHz, DMSO-d₆): δ 1.46 (m, 2H), 1.62 (m, 4H),3.01 (m, 2H), 3.64 (s, 3H), 4.14 (s, 3H), 4.66 (m, 1H), 6.61 (d, 2H),6.81 (s, 2H), 6.88 (s, 1H), 7.18 (d, 2H), 7.31 (d, 2H), 7.44 (d, 2H),7.60 (m, 1H), 8.19 (s, 3H).

6.17. Synthesis of(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrimidin-4-yl)phenyl)propanoicacid

Sodium tiracetoxyl-borohydride (985 mg, 4.65 mmol) was added to asolution of 6-chloro-pyrimidin-4-ylamine (200 mg, 1.55 mmol) and3-cyclopentyloxy-4-methoxy-benzaldehyde (682 mg, 3.1 mmol) in 25 ml ofDCE. 1 ml of HOAc was added, and the mixture was stirred overnight at50° C., followed by addition of 25 ml of DCE. The organic phase waswashed with water, and the product was purified with column (silica gel,hexane:EtOAc 5:1) to give 64 mg of(6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine,yield 12%.

An Emrys process vial (2-5 ml) for microwave was charged with(6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64mg, 0.19 mmol), 4-borono-L-phenylalanine (40 mg, 0.19 mmol) and 2 ml ofacetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to abovesolution followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes with microwave. Aftercooling, the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mgof2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-propionicacid, yield 6%. ¹H-NMR (400 MHz, DMSO-d₆): δ 1.46 (m, 2H), 1.62 (m, 4H),3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.20 (m, 1H), 4.46 (d, 2H),4.68 (m, 1H), 6.82 (t, 2H), 6.87 (d, 2H), 7.40 (d, 2H), 7.90 (s, 2H),8.25 (s, 2H), 8.6 (s, 1H).

6.18. Synthesis of(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrazin-2-yl)phenyl)propanoicacid

Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to asolution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml ofDCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50°C., followed by addition of another 50 ml of DCE. The organic phase waswashed with water, and the product was purified with column (silica gel,hexane:EtOAc 6:1) to give 50 mg of(6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield10%.

An Emrys process vial (2-5 ml) for microwave was charged with(6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml ofacetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to thesolution followed by 5 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, and the product was purified withPrep-LC to give 5.5 mg of2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionicacid, yield 6%. ¹H-NMR (400 MHz, DMSO-d₆): δ 1.46 (m, 2H), 1.62 (m, 4H),3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.0 (m, 1H), 4.45 (d, 2H),4.65 (m, 1H), 6.90 (s, 2H), 6.95 (s, 1H), 7.32 (d, 2H), 7.60 (t, 1H),7.90 (s, 1H), 7.95 (d, 2H), 8.25 (s, 1H).

6.19. Synthesis of(S)-2-Amino-3-(4-(5-((4′-methylbiphenyl-2-yl)methylamino)pyrazin-2-yl)phenyl)propanoicacid

Sodium tiracetoxyl borohydride (215 mg, 1.02 mmol) was added to thesolution of 4′-methyl-biphenyl-2-carbaldehyde and5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added andthe mixture was stirred overnight at room temperature, followed byaddition of 5 ml of DCE. The organic phase was washed with water, andpurified with column (silica gel, hexane:EtOAc 6:1) to give 100 mg of(5-bromo-pyrazin-2-yl)-(4′-methyl-biphenyl-2-ylmethyl)-amine, yield 55%.

An Emrys process vial (2-5 ml) for microwave was charged with(5-bromo-pyrazin-2-yl)-(4′-methyl-biphenyl-2-ylmethyl)-amine (25 mg,0.071 mmol), 4-borono-L-phenylalanine (22 mg, 0.11 mmol) and 1 ml ofacetonitrile. Aqueous sodium carbonate (1 ml, 1M) was added to thesolution followed by 5 mol percentdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, and the product was purified withPrep-LC to give 19 mg of2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionicacid, yield 63%. ¹H-NMR (400 MHz, CD₃OD): δ 2.22 (s, 3H), 3.09 (m, 1H),3.25 (m, 1H), 4.18 (t, 1H), 4.40 (s, 2H), 7.07 (d, 2H), 7.14 (m, 3H),7.24 (m, 4H), 7.36 (m, 1H), 7.72 (d, 2H), 7.84 (s, 1H), 8.20 (d, 1H).

6.20. Synthesis of(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-phenylethoxy)-pyrimidin-4-yl)phenyl)propanoicacid

NaH (60%, 120 mg, 3.0 mmol) was added to a solution of2,2,2-trifluoro-1-phenyl-ethanol (350 mg, 2.03 mmol) in 5 ml of THF. Themixture was stirred for 20 minutes at room temperature.4,6-Dichloro-pyrimidine (300 mg, 2.03 mmol) was added and then thereaction mixture was heated at 70° C. for 1 hour. After cooling, the THFwas evaporated to provide a residue, which was dissolved in 15 ml ofEtOAc, and then washed with water, and dried over sodium sulfate. Thesolvent was removed by rotovap to give 550 mg of4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine, yield 95%.

An Emrys process vial (2-5 ml) for microwave was charged with4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine (30 mg, 0.11mmol), 4-borono-L-phenylalanine (32 mg, 0.16 mmol), 1 ml of acetonitrileand 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added toabove solution followed by 10 mol percent of POPd₂ (dihydrogendi-μ-chlorodichlorobis(di-tert-butylphosphinito-κP) dipalladate. Thereaction vessel was sealed and heated to 120° C. for 30 minutes bymicrowave. After cooling, the reaction mixture was evaporated todryness. The residue was dissolved in 2.5 ml of methanol, and theproduct was purified with Prep-LC to give 4.8 mg of2-amino-3-{4-[6-(2,2,2-trifluoro-1phenyl-ethoxy)-pyrimidin-4-yl]-phenyl}-propionicacid, yield 11%. ¹H-NMR (400 MHz, CD₃OD): δ 3.20 (m, 1H), 3.40 (m, 1H),4.25 (t, 1H), 6.82 (dd, 1H), 7.43 (m, 5H), 7.57 (s, 1H), 7.60 (m, 2H),8.10 (d, 2H), 8.75 (s, 1H).

6.21. Synthesis of(2S)-2-Amino-3-(4-(6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid

Tetrabutylammonium fluoride (TBAF: 0.1 ml, 1M) in THF was added to asolution of 3,4-difluro-benzaldehyde (1.42 g, 10 mmol) and(trifluromethyl)trimethylsilane (1.70 g, 12 mmol) in 10 ml THF at 0° C.The mixture was warmed up to room temperature and stirred for 4 hours.The reaction mixture was treated with 12 ml of 1M HCl and stirredovernight. The product was extracted with dicloromethane (3×20 ml), theorganic layer was combined and passed through a pad of silica gel. Theorganic solvent was evaporated to give 1.9 g of1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethanol, yield 90%.

NaH (80 mg, 60%, 3.0 mmol) was added to a solution of1-(3,4-Difluoro-phenyl)-2,2,2-trifluoro-ethanol (212 mg, 1 mmol) in 5 mlof THF, the mixture was stirred for 20 minutes at room temperature.4,6-Dichloro-pyrimidine (149 mg, 1 mmol) was added and then the reactionmixture was heated at 70° C. for 1 hour. After cooling, THF wasevaporated. The residue was dissolved in 15 ml of EtOAc, and then washedwith water, dried over sodium sulfate. The solvent was removed byrotovap to give 230 mg of4-chloro-6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine,yield 70%.

An Emrys process vial (2-5 ml) for microwave was charged with4-chloro-6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine(33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml ofacetonitrile and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M)was added to above solution followed by 5 mol % ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 150° C. for 5 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol, then purified with Prep-LC to give 10mg of2-amino-3-(4-{6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyridin-4-yl}-phenyl)-propionicacid, yield 21%. ¹H-NMR (400 MHz, CD₃OD): δ 3.11 (m, 1H), 3.27 (m, 1H),4.19 (dd, 1H), 6.78 (q, 1H), 7.26 (m, 2H), 7.35 (d, 3H), 7.49 (m, 2H),8.02 (d, 2H), 8.66 (s, 1H).

6.22. Synthesis of(S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)-pyrazin-2-yl)phenyl)propanoicacid

A mixture of 3-cyclopentyloxy-4-methoxy-benzaldehyde (417 mg, 1.895mmol), 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), sodiumtriacetoxyborohydride (1.5 eq) and glacial acetic acid (3 eq) indichloromethane (10 ml) was stirred at room temperature overnight. Thenthe reaction mixture was diluted with ethyl acetate, and washed withwater. The oraganic layer was dried over MgSO₄ and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby ISCO (SiO₂ flash column chromatography) (Hexane/ethyl acetate=100/0to 3/2) to give about 400 mg of6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. Yield:61%.

To a 5 ml microwave vial, the above6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg,0.132 mmol), 4-borono-L-phenylalanine (30 mg, 0.144 mmol), Na₂CO₃ (31mg, 0.288 mmol), acetonitrile (2 ml) and water (2 ml). Dichlorobis(triphenylphosphine)-palladium (5 mg, 0.007 mmol) was added. The vialwas capped and stirred at 150° C. for 5 minutes under microwaveradiation. The reaction mixture was cooled, filtered through a syringefilter and then separated by a reverse phase preparative-HPLC usingYMC-Pack ODS 100×30 mm ID column (MeOH/H₂O/TFA solvent system). The purefractions were concentrated in vacuum. The product was then suspended in5 ml of water, frozen and lyophilized to give the title compound as atrifluoro salt (12 mg, 20%). ¹H NMR (CD₃OD) δ 8.41 (s, 1H), 7.99 (s,1H), 7.83 (d, J=9.0 Hz, 2H), 7.37 (d, J=6.0 Hz, 2H), 6.90-6.95 (m, 3H),4.78 (m, 1H), 4.50 (s, 2H), 4.22-4.26 (m, 1H), 3.79 (s, 3H), 3.12-3.39(m, 2H), 1.80-1.81 (m, 6H), 1.60 (m, 2H). M+1=463.

6.23. Synthesis of(S)-2-Amino-3-(4-(5-((3-(cyclopentyloxy)-4-methoxybenzyl)-(methyl)amino)pyrazin-2-yl)phenyl)propanoicacid

To a solution of(6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (70 mg,0.185 mmol) in acetonitrile (10 ml) was added formaldehyde (18.5 mmol)and sodium cyanoborohydride (17 mg, 0.278 mmol). Then, concentratedaqueous HCl was added dropwise until the pH≈2. The mixture was stirredfor about 6 hours at room temperature. It was then diluted with ethylacetate, washed with water (3×5 ml), dried over MgSO₄. The solvent wasremoved by vacuum to give 70 mg of crude product5-(bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-methyl-amine(95% crude yield), which was used in the next step without furtherpurification.

The5-(bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-methyl-amine(37 mg, 0.094 mmol) was subjected to a Suzuki coupling reaction asdescribed above to afford 6 mg of the title compound. Yield:13%. ¹H NMR(CD₃OD) δ 8.59 (s, 1H), 8.12 (s, 1H), 7.85 (d, 2H), 7.39 (d, 2H),6.81-6.91 (m, 3H), 4.72 (m, 1H), 4.30 (m, 1H), 3.79 (s, 3H), 3.20-3.40(m, 2H), 3.18 (s, 3H), 3.79 (s, 3H), 1.80 (m, 6H), 1.58 (m, 2H).M+1=477.

6.24. Synthesis of(S)-2-Amino-3-(4-(5-((1,3-dimethyl-1H-pyrazol-4-yl)methylamino)pyrazin-2-yl)phenyl)propanoicacid

A mixture of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (142 mg, 1.145mmol), 2-amino-5-bromopyrazine (200 mg, 1.149 mmol), boranetrimethylamine complex (126 mg, 1.73 mmol) and glacial acetic acid (137mg, 2.29 mmol) in anhydrous methonol (3 ml) was stirred at roomtemperature overnight. The reaction mixture was then diluted with ethylacetate, washed with water, dried over MgSO₄ and filtered. The filtratewas concentrated to give 300 mg of(5-bromo-pyrazin-2-yl)-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)amine ascrude product, which was used for next step reaction without furtherpurification. Crude yield: 93%.

The (5-bromo-pyrazin-2-yl)-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)amine (40mg, 0.142 mmol) was used in the Suzuki coupling reaction described aboveto afford 19 mg of of the title compound. Yield: 36.5%. ¹H NMR (CD₃OD) δ8.48 (s, 1H), 8.05 (s, 1H), 7.87 (d, 2H), 7.39 (d, 2H), 6.10 (s, 1H),4.81 (s, 2H), 4.30 (m, 1H), 3.83 (s, 3H), 3.11-3.38 (m, 2H), 2.10 (s,3H). M+1=367.

6.25. Synthesis of(S)-2-Amino-3-(4-(4-amino-6-((S)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yloxy)phenyl)propanoicacid

To a 250 ml flask, R-(+)-1-(2-naphthyl)ethylamine (400 mg, 2.424 mmol),2-amino-4,6-dichloro triazine (373 mg, 2.181 mmol), anhydrous1,4-dioxane (40 ml), and N,N-diisopropylethylamine (1 ml, 5.732 mmol)were added and heated to mild reflux for about 4 hours. The reaction wasmonitored carefully in order to avoid the formation of the disubstitutedproduct. (It was observed that the longer the reaction, the moredisubstituted product is formed). After 4 hours, the reaction mixturewas cooled and the solvent was removed under reduced pressure. Water wasadded to the residue, and the solution was sonicated for 2-3 minutes.The solvent was then filtered, washed with water and dried to give 540mg (83% crude yield) of the mono-chloride,6-chloro-N-(1-naphthalen-2-yl-ethyl)-[1,3,5]triazine-2,2-diamine, whichwas used for the next step reaction without further purification.

A mixture of6-chloro-N-(1-naphthalen-2-yl-ethyl)-[1,3,5]triazine-2,2-diamine (90 mg,0.300 mmol), 2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionicacid tert-butyl ester (102 mg, 0.303 mmol) and potassium carbonate (82mg, 0.594 mmol) in isopropanol (8 ml) was refluxed over night. Thesolvent was removed under reduced pressure and the residue was suspendedin ethyl acetate. The solid was filtered and washed with ethyl acetate.The filtrate was concentrated and then redissolved in a mixture ofmethanol/water (90:10) and purified by a preparative-LC using a SunfireC18 OBD 100×30 mm ID column (MeOH/H₂O/TFA solvent system). The purefractions were combined and concentrated to give 50 mg of pure product,3-{4-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2yloxy]-phenyl}2-tert-butoxycarbonylamino-propionicacid tert-butyl ester, (28% yield).

The above product (50 mg, 0.083 mmol) was dissolved in trifluoro aceticacid/dichloromethane (8 ml/2 ml) and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue wasthen redissolved in a mixture of methanol/water (90:10) and purified bya preparative-LC using a Sunfire C18 OBD 100×30 mm ID column(MeOH/H₂O/TFA solvent system). The pure fractions were combined andconcentrated under reduced pressure to afford about 4 ml, which wasfrozen and lyophilized to give 4 mg of the title compound as a TFA salt(11% yield). ¹H NMR (CD₃OD) δ 7.37-7.81 (m, 8H), 7.19 (m, 2H), 6.98 (m,1H), 5.37 (m, 1H), 4.19 (m, 1H), 3.17-3.38 (m, 2H), 1.56 (m, 3H).M+1=445.

6.26. Synthesis of(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(biphenyl-2-yl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid

A mixture of 1-biphenyl-2-yl-2,2,2-trifluoro-ethanone (300 mg, 1.2mmol), borane tetrahydrofuran complexes (1.2 ml, 1M in THF, 1.2 mmol)and S-2-methyl-CBS-oxazaborolidine (0.24 ml, 1M in toluene, 0.24 mmol)in THF (8 ml) was stirred at room temperature over night. Several dropsof concentrated HCl were added and the mixture was stirred for 30minutes. The product was purified by SiO₂ chromatography (hexane/ethylacetate=100/0 to 3/1) to give 290 mg of1-biphenyl-2-yl-2,2,2-trifluoro-ethanol (96% yield).

The above alcohol (290 mg, 1.151 mmol) was dissolved in anhydrous THF(10 ml). Sodium hydride (55 mg, 1.375 mmol) was added all at once, andthe mixture was stirred at room temperature for 30 minutes. The solutionwas then transferred into a flask that contained a suspension of2-amino-4,6-dichloro-triazine (190 mg, 1.152 mmol) in THF (20 ml). Themixture was stirred at room temperature overnight. Water was added andthe mixture was then diluted with ethyl acetate. The organic layer waswashed with water, dried over MgSO₄ and then concentrated to give 400 mgof crude product2-amino-4-(1-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine.

The 2-amino-4-(1-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine(40 mg, 0.105 mmol) was subjected to the same Suzuki coupling reactionas described above to afford 5 mg of the title compound. Yield: 9.4%. ¹HNMR (CD₃OD) δ 8.18 (d, 2H), 7.86 (m, 1H), 7.40-7.52 (m, 9H), 7.32 (m,1H), 7.07 (m, 1H), 4.32 (m, 1H), 3.22-3.41 (m, 2H). M+1=510.

6.27. Synthesis of(2S)-2-Amino-3-(4-(4-amino-6-(1-(6,8-difluoronaphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

In a three-neck flask, copper iodine (CuI) (299 mg, 1.515 mmol) andlithium chloride (LiCl) (145 mg, 3.452 mmol) were added under nitrogento anhydrous THF (60 ml). The mixture was stirred at room temperatureuntil a pale yellow solution was obtained. After cooling to 0° C.,methyl vinyl ketone and chlorotrimethylsilane were added, and themixture was stirred until an orange color was observed (˜20 min). Aftercooling to about −40° C., a solution of 3,5-difluorophenylmagnesiumbromide (27.65 ml, 13.8 mmol) in THF (0.5M) was slowly added. Thereaction mixture was stirred at about −40° C. for 0.5 hours, then thecold bath was removed and the temperature was allowed to rise slowly toroom temperature. The solvent was evaporated and the residue wasextracted with hexane (4×20 ml). The collected extractions were washedwith cold 10% aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasevaporated at reduced pressure to afford3,5-difluorophenyl-1-trimethylsilyloxyalkene (2.03 g, 7.929 mmol, 57%crude yield), which was used in the successive reaction without furtherpurification.

Powered calcium carbonate (3.806 g, 38.06 mmol) and ethyl vinyl ether(2.184 g, 30.329 mmol) were added to a solution of ceric ammoniumnitrate (10.430 g, 19.033 mmol) in methanol (40 ml) under nitrogenatmosphere. To the resulting suspension was added a solution of abovemade 3,5-difluorophenyl-1-trimethylsilyloxyalkene (2.03 g, 7.929 mmol)in ethyl vinyl (6 ml, 4.518 g, 62.75 mmol) dropwise under vigorousstirring, and the mixture was stirred at room temperature overnight. Thesolid was filtered through a celite layer, and the filtrate wasconcentrated to one-fourth of its initial volume. The resulting thickmixture was slowly poured, under vigorous stirring, into 1:1 v/v diethylether-10% aqueous NaHCO₃. The precipitate was filtered off, the etherealsolution was separated, and the solvent was evaporated at reducedpressure to give clear liquid. The solution of resulting liquid (amixture of acyclic and cyclic acetates) in methanol (4 ml) was addeddropwise to a suspension of dichlorodicyanobenzoquinone (1.77 g, 7.797mmol) in 80% aqueous sulfuric acid at 0° C. After the addition wascomplete, the ice bath was removed and stirring was continued for 30minutes. The mixture was poured into ice water; and the resulting brownprecipitate was filtered and dissolved in acetone. Silica gel was addedto make a plug, and the crude product was purified by chromatography(hexane/ethyl acetate=100/0 to 3/1) to give 760 mg of1-(5,7-difluoro-naphthalen-2-yl)-ethanone (48% in two-step yield) as alight yellow solid.

The above ketone (760 mg, 3.689 mmol) was dissolved in methanol (40 ml).Then, ammonium acetate (2.841 g, 36.896 mmol), sodium cyanoborohydride(232 mg, 3.389 mmol) and molecular sieves (3 Å, 7.6 g) were added. Themixture was stirred at room temperature for two days. The solid wasfiltered and the filtrate was concentrated. The residue was dissolved inwater and concentrated aqueous HCl was added dropwise until the pH≈2.The mixture was then extracted with ethyl acetate to remove theunfinished ketone and other by-products. The water layer was basified topH≈10 with aqueous sodium hydroxide (1M), and was extracted withdichloromethane and the organic layers were combined, dried overmagnesium sulfate and concentrated to afford 290 mg of1-(5,7-difluoro-naphthalen-2-yl)-ethylamine (38% yield).

The fresh made amine (290 mg, 1.401 mmol) was added directly to asuspension of 2-amino-4,6-dichloro triazine (277 mg, 1.678 mmol) inanhydrous 1,4-dioxane (60 ml), and followed by addition ofN,N-diisopropylethylamine (1 ml, 5.732 mmol). The mixture was heated tomild reflux for about 3 hours. The reaction mixture was then cooled, andthe solvent was removed under reduced pressure. To the residue was addedwater and the mixture was sonicated for 2-3 minutes. The resulting solidwas filtered and washed with water and dried to give 395 mg (60% crudeyield) of6-chloro-N-[1-(6,8-difluoro-naphthalen-2-yl-ethyl]-[1,3,5]triazine-2,4-diamine,which was used for the next step reaction directly without furtherpurification.

The above made mono-chloride (48 mg, 0.144 mmol) was subjected to thesame Suzuki coupling reaction as described above to afford 12 mg of thetitle product. Yield: 17.9%. ¹H NMR (CD₃OD) δ 8.14-8.22 (m, 2H), 8.05(m, 1H), 7.92 (m, 1H), 7.63 (m, 1H), 7.32-7.51 (m, 3H), 7.11 (m, 1H),5.48 (m, 1H), 4.13 (m, 1H), 3.13-3.41 (m, 2H), 1.66 (d, 3H). M+1=465.

6.28. Synthesis of(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid

To a mixture of 3′-methyl-1-biphenyl-2-carbaldehyde (500 mg, 2.551 mmol)and trifluoromethyl trimethylsilane (435 mg, 3.061 mmol) in THF (3 ml)was added tetrabutyl ammonium fluoride (13 mg, 0.05 mmol) at 0° C. Thetemperature was allowed to warm to room temperature. The mixture wasstirred for 5 hours at room temperature, then diluted with ethylacetate, washed with water and brine and dried by MgSO₄. The solvent wasremoved under reduced pressure to give 660 mg (97% crude yield) of2,2,2-trifluoro-1-(3′-methyl-biphenyl-2-yl)-ethanol as crude product,which was used for next step without further purification.

The above-made alcohol (660 mg, 2.481 mmol) was dissolved in anhydrous1,4-dioxane (10 ml). Sodium hydride (119 mg, 60% in mineral oil, 2.975mmol) was added all at once and the mixture was stirred at roomtemperature for 30 minutes. The solution was transferred into a flaskcontaining a suspension of 2-amino-4,6-dichloro-triazine (491 mg, 2.976mmol) in 1,4-dioxane (70 ml). The mixture was stirred at roomtemperature for 6 hours. The solvent was removed, and the residue wassuspended in ethyl acetate, which was washed with water, dried overMgSO₄ and then concentrated to give 790 mg of crude product, whichcontained about 57% of the desired product2-amino-4-(1-(3′-methyl-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazineand about 43% byproduct (the bisubstituted product). The crude productwas used without further purification.

The2-amino-4-(1-(3′-methyl-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine(98 mg, 57% purity, 0.142 mmol) was used to run the same Suzuki couplingreaction as described above to afford 9 mg of the title compound.Yield:12.0%. ¹H NMR (CD₃OD) δ 8.09 (m, 2H), 7.85 (m, 1H), 7.50 (m, 2H),7.28-7.43 (m, 5H), 7.17-7.26 (m, 2H), 7.18 (m, 1H), 3.85 (m, 1H),3.08-3.44 (m, 2H), 2.33 (s, 3H). M+1=524.

6.29. Synthesis of(S)-2-Amino-3-(4-(5-(3,4-dimethoxyphenylcarbamoyl)-pyrazin-2-yl)phenyl)propanoicacid

To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) andtriethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-5° C. Themixture was allowed to stir at room temperature for 3 hours. The mixturewas diluted with methylene chloride (20 ml), washed with saturatedNaHCO₃ (20 ml), brine (20 ml), dried (anhyd. Na₂SO₄) and concentrated toget 0.42 g of crude 5-chloro-pyrazine-2 carboxylic acid(3,4-dimethoxy-phenyl)-amide, which was directly used in the nextreaction.

5-Chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide (0.18g, 0.61 mmol), L-p-borono phenylalanine (0.146 g, 0.70 mmol), CH₃CN (2.5ml), H₂O (2.5 ml), Na₂CO₃ (0.129 g, 1.22 mmol) were combined in amicrowave vial. The mixture was sealed and kept at 150° C. for 5minutes. The mixture was filtered and concentrated. The residue wasdissolved in methanol/water (1:1) and purified by preparative HPLC,using MeOH/H₂O/TFA as solvent system to afford2-amino-3-{4-[5-(3,4-dimethoxy-phenylcarbomyl)-pyrazin-2-yl]-phenyl}-propionicacid as a TFA salt (HPLC: Method A, Retention time=2.846 min, LCMS M+1423). ¹H NMR (400 MHz, DMSO-d₆) δ 3.10-3.30 (m, 2H), 3.72 (d, 6H), 4.05(m, 1H), 7.42-7.62 (m, 4H), 8.22 (m, 3H), 9.30 (m, 2H).

6.30. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(4-(2-(trifluoromethyl)phenyl)-piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid

2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol),4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol),and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of1,4-dioxane (5 ml) and H₂O (5 ml) in a 20 ml microwave vial. The mixturewas stirred at 210° C. for 20 minutes in a microwave reactor. Solventwas removed and the residue was dissolved in 5% methanol in CH₂Cl₂ (20ml), dried over Na₂SO₄ and concentrated to get the crude intermediate,4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine(0.42 g) which was directly used in the following step.

The crude intermediate (0.42 g), L-p-borono-phenylalanine (0.209 g, 1mmol), sodium carbonate (0.210 g, 2 mmol), anddichlorobis(triphenylphosphine)-palladium(II) (35 mg, 0.05 mmol) weredissolved in a mixture of MeCN (2.5 ml) and H₂O (2.5 ml) in a 10 mlmicrowave vial. The vial was sealed and stirred in a microwave reactorat 150° C. for 6 minutes. The mixture was filtered, and the filtrate wasconcentrated. The residue was dissolved in MeOH and H₂O (1:1) andpurified by preparative HPLC using MeOH/H₂O/TFA as the solvent system toafford2-amino-3-(4-{4-(2-trifluoromethyl-phenyl)-piperidine-1-yl]-pyrimidin-4-yl}-phenyl)-propionicacid as a TFA salt. HPLC: Method A, Retention time=3.203 min. LCMS M+1486. ¹H NMR (400 MHz, CD₃OD) δ 1.80-2.20 (m, 5H), 3.0-3.16 (m, 2H),3.22-3.42 (m, 2H), 4.22 (t, 1H), 4.42-4.54 (m, 1H), 5.22-5.34 (m, 1H),6.80 (s, 1H), 7.40 (t, 1H), 7.50-7.60 (m, 4H), 7.68 (d, 1H), 7.82 (d,2H).

6.31. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)pyrimidin-4-yl)phenyl)propanoicacid

2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol),(R)-(+)-1-(2-naphthyl)-ethylamine (0.171 g, 1 mmol), and cesiumcarbonate (0.358 g, 1.1 mmol) were dissolved in a mixture of 1,4-dioxane(4 ml) and H₂O (4 ml) in a 20 ml microwave vial. The vial was sealed andstirred at 210° C. for 20 minutes in a microwave reactor. Solvent wasremoved and the residue was dissolved in CH₂Cl₂ (50 ml), washed withwater (20 ml), brine (20 ml), dried (Na₂SO₄) and concentrated to affordthe crude intermediate,6-chloro-N-4-(naphthalene-2-yl-ethyl)-pyrimidine-2,4-diamine (0.270 g)which was directly used in the following step.

The crude intermediate (0.27 g), L-p-borono-phenylalanine (0.210 g, 1mmol), sodium carbonate (0.210 g, 2 mmol), anddichlorobis(triphenylphosphine)-palladium(II) (25 mg, 0.036 mmol) weredissolved in a mixture of MeCN (2.5 ml) and H₂O (2.5 ml) in a microwavevial. The vial was sealed and stirred in the microwave reactor at 150°C. for 6 minutes. The mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in MeOH and H₂O (1:1) andpurified by preparative HPLC using MeOH/H₂O/TFA as the solvent system toafford 2amino-3-{4-[2-amino-6-(1-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-phenyl}-propionicacid as a TFA salt. HPLC: Method A, Retention time=3.276 min. LCMS M+1428. ¹H NMR (400 MHz, CD₃OD) δ 1.68 (d, 3H), 3.22-3.40 (m, 2H), 4.30 (t,1H), 5.60 (q, 1H), 6.42 (s, 1H), 7.42-7.54 (m, 5H), 7.72 (m, 2H),7.82-7.84 (m, 4H).

6.32. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(methyl((R)-1-(naphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)propanoicacid

2-Amino 4,6-dichloro pyrimidine (0.327 g, 2 mmol),methyl-(1-naphthalen-2-yl-ethyl)-amine (0.360 g, 2 mmol), and cesiumcarbonate (0.717 g, 2.2 mmol) were dissolved in a mixture of 1,4-dioxane(7.5 ml) and H₂O (7.5 ml) in a 20 ml microwave vial. The vial was sealedand stirred at 210° C. for 20 minutes in a microwave reactor. Solventwas removed and the residue was dissolved in CH₂Cl₂ (50 ml), washed withwater (20 ml), brine (20 ml) dried (Na₂SO₄) and concentrated to get thecrude intermediate,6-chloro-N-4-methyl-N-4-(1-napthalen-2-yl-ethyl)-pyrimidine-2,4-diamine(0.600 g), which was directly used in the following step.

The crude intermediate (0.30 g), L-p-borono-phenylalanine (0.210 g, 1mmol), sodium carbonate (0.210 g, 2 mmol), anddichlorobis(triphenylphosphine)-palladium(II) (25 mg, 0.036 mmol) weredissolved in a mixture of MeCN (2.5 ml) and H₂O (2.5 ml) in a microwavevial. The vial was sealed and stirred in the microwave reactor at 150°C. for 6 minutes. The mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in MeOH and H₂O (1:1) andpurified by preparative HPLC using MeOH/H₂O/TFA as the solvent system toafford2-amino-3-(4-{2-amino-6-[methyl-(1-naphthalen-2-yl-ethyl)amino]-pyrimidin-4-yl}-phenyl)-propionicacid as a TFA salt (HPLC: Method C, Retention time=2.945 min, LCMS M+1442) ¹H NMR (400 MHz, CD₃OD) δ 1.70 (m, 3H), 2.92 (s, 3H), 3.22-3.42 (m,2H), 4.28 (m, 1H), 6.60 (s, 1H), 6.72 (m, 1H), 7.40-7.92 (m, 11H).

6.33. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid

2-Amino 4,6-dichloro pyrimidine (0.096 g, 0.6 mmol),2,2,2-trifluoro-1-(6-methoxy-naphthalen-2-yl)-ethanol (0.140 g, 0.55mmol), and NaH (96 mg, 0.60 mmol) were added to anhydrous dioxane (20ml) under a nitrogen atmosphere. The reaction was stirred at 80° C. for12 hours, cooled to room temperature, and quenched with water (0.2 ml).The reaction mixture was concentrated, and the residue dissolved inCH₂Cl₂ (50 ml), washed with water (20 ml), brine (20 ml) dried (Na₂SO₄)and concentrated to afford the crude intermediate,4-chloro-6-[2,2,2-trifluoro-1-(6-methoxy-naphthalene-2-yl)-ethoxy]-pyrimidin-2-ylamine(0.22 g) which was directly used in the following step.

The crude intermediate (0.22 g), L-p-borono-phenylalanine (0.126 g, 0.6mmol), sodium carbonate (0.126 g, 1.2 mmol), anddichlorobis(triphenylphosphine)-palladium(II) (15 mg, 0.021 mmol) weredissolved in a mixture of MeCN (2.0 ml) and H₂O (2.0 ml) in a microwavevial. The vial was sealed and stirred in the microwave reactor at 150°C. for 6 minutes. The mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in MeOH and H₂O (1:1) andpurified by preparative HPLC using MeOH/H₂O/TFA as the solvent system toafford2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(6-methoxy-naphthalen-2-yl)-ethoxy]-pyrimidin-4-yl]-phenyl)-propionicacid as a TFA salt (HPLC: Method C, Retention time=3.190 min. LCMS M+1513. ¹H NMR (400 MHz, CD₃OD) δ 3.22-3.42 (m, 2H), 3.86 (s, 3H), 4.32(1H), 6.88 (m, 1H), 6.92 (1H), 7.20 (dd, 1H), 7.26 (s, 1H), 7.50 (d,2H), 7.63 (d, 1H), 7.80-7.90 (m, 4H), 8.05 (s, 1H).

6.34. Synthesis of(S)-2-Amino-3-(4-(5-(biphenyl-4-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid

4-Phenylbenzaldehyde (0.3 g, 1.65 mmol) and 2-amino-5-bromopyrazine(0.24 g, 1.37 mmol) were treated with Na(OAc)₃BH (0.44 g, 2.06 mmol) indichloroethane (7.0 mls) and acetic acid (0.25 mls) for 18 hours at roomtemperature. The mixture was diluted with dichloromethane, washed with1.0 N NaOH, washed with brine, dried over MgSO₄, and concentrated.Chromatography (SiO₂, EtOAc:Hex, 1:1) gave 0.18 g ofN-(biphenyl-4-ylmethyl)-5-bromopyrazin-2-amine.

N-(biphenyl-4-ylmethyl)-5-bromopyrazin-2-amine (60 mg, 0.176 mmol),L-p-boronophenylalanine (37 mg, 0.176 mmol), palladiumtriphenylphosphinedichloride (3.6 mg, 0.0052 mmol), Na₂CO₃ (37 mg, 0.353 mmol),acetonitrile (1.25 mls) and water (1.25 mls) were heated in a microwavereactor at 150° C. for 5 minutes. The mixture was concentrated,dissolved in 1.0 N HCl, washed twice with ether, concentrated andpurified by preprative HPLC to give 41 mgs of the title compound.M+1=425; ¹H NMR (CD₃OD) δ 8.42 (s, 1H), 8.05 (s, 1H), 7.92 (d, 2H), 7.58(d, 4H), 7.40 (m, 7H), 4.60 (s, 2H), 4.25 (m, 1H), 3.40 (m, 1H), 3.20 (m, 1H).

6.35. Synthesis of(S)-2-Amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid

2-Napthaldehyde (0.6 g, 3.84 mmol) and 2-amino-5-bromopyrazine (0.56 g,3.201 mmol) were treated with Na(OAc)₃BH (1.02 g, 4.802 mmol) indichloroethane (15.0 mls) and acetic acid (0.5 mls) for 18 hours at roomtemperature. The mixture was diluted with dichloromethane, washed with1.0 N NaOH, washed with brine, dried over MgSO₄, and concentrated.Chromatography (SiO₂, EtOAc:Hex, 1:1) gave 0.49 g5-bromo-N-(naphthalen-2-ylmethyl)pyrazin-2-amine.

5-Bromo-N-(naphthalen-2-ylmethyl)pyrazin-2-amine (0.2 g, 0.637 mmol),L-p-boronophenylalanine (0.13 g, 0.637 mmol),palladiumtriphenylphosphine dichloride (13 mg, 0.019 mmol), Na₂CO₃ (0.13g, 1.27 mmol), acetonitrile (5 mls) and water (5 mls) were heated in amicrowave reactor at 150° C. for 5 minutes. The mixture wasconcentrated, dissolved in 1.0 N HCl, washed twice with ether,concentrated, dissolved in methanol, filtered and concentrated to yield0.12 g of the captioned compound. M+1=399; ¹H NMR (CD₃OD) δ 8.51 (s,1H), 8.37 (s, 1H), 7.90 (m, 6H), 7.50 (m, 5H), 4.85 (s, 2H), 4.30 (t,1H), 3.38 (m, 1H), 3.22 (m, 1H).

6.36. Synthesis of(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid

(S)-2-Amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid (0.15 g, 0.345 mmol) was treated with triethylamine (87 mg, 0.862mmol), and boc-anhydride (84 mg, 0.379) in dioxane (3 ml) and H₂O (3 ml)at 0° C. The mixture was warmed to room temperature and stirredovernight. The mixture was concentrated, and partitioned between EtOAcand H₂O. The aqueous phase was acidified to pH=1 with 1.0 N HCl andextracted with EtOAc. The organics were combined, washed with brine,dried over MgSO₄, and concentrated to yield 48 mg of the captionedcompound.

6.37. Synthesis of (S)-2-Morpholinoethyl2-amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoate

(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid (48 mg, 0.090 mmol), 4-(2-hydroxyethyl)morpholine (12 mg, 0.090mmol), triethylamine (18 mg, 0.180 mmol), andbenzotriazole-1-yloxytris(dimethylamino)-phosphonium hexaflurophosphate(BOP, 18 mg, 0.090 mmol), in dichloromethane (3.0 ml) were stirred atroom temperature for 5 hours. Additional triethylamine (18 mg, 0.180mmol) and BOP (18 mg, 0.090 mmol) were added, and the mixture wasstirred overnight. The mixture was concentrated and purified via prepHPLC to give 2 mg of the captioned compound.

6.38. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid

To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50mls) at 0° C. was added NaBH₄ (1.5 g, 39.52 mmol). The mixture waswarmed to room temperature and stirred for 1 hour. The reaction wascomplete by TLC (CH₂Cl₂). The mixture was quenched with H₂O, rotaryevaporated to remove most of the THF, and extracted 2 times with CH₂Cl₂.The organics were combined, washed with brine, concentrated to a smallvolume and filtered through a plug of silica gel. The silica was washedwith CH₂Cl₂ to elute the product, and the resulting solution wasconcentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol.Yield 92%.

To Pd(PPh₃)₄ (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesiumbromide (55 mls, 1.0 M in THF, 55 mmol) at 0° C. over 15 minutes. Theice bath was removed and the mixture was stirred for 30 minutes.1-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50mls) was added over 10 minutes. The mixture was heated to reflux for 3hours and was shown complete by LC (Sunfire column, TFA). The mixturewas cooled, quenched with H₂O, rotary evaporated to remove most of theTHF, and extracted 3 times with CH₂Cl₂. The organics were combinedwashed with brine, dried over MgSO₄, and concentrated. Chromatography(SiO₂, CH₂Cl₂) gave 4.64 g of2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol. Yield 94%.

To 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol (1.4 g, 5.18 mmol)in THF (50 mls) at 0° C. was added NaH (60% in mineral oil, 0.31 g, 7.77mmol). The ice bath was removed and the mixture was stirred for 30minutes. 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.22 mmol) in THF (25mls) was added at once. The mixture was heated to 50° C. for 5 hours.The reaction was complete by LCMS (Sunfire, TFA). The mixture wascooled, quenched with brine, and extracted 3 times with CH₂Cl₂. Theorganics were combined, washed with brine, dried over MgSO₄, andconcentrated. Chromatography (SiO₂, CH₂Cl₂) afforded 1.48 g of4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine.Yield 73%.

4-Chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine(0.75 g, 1.89 mmol), L-p-boronophenylalanine (0.47 g, 2.26 mmol),Pd(PPh₃)₂Cl₂ (79 mgs, 0.113 mmol), Na₂CO₃ (0.44 g, 4.15 mmol),acetonitrile (10 mls), and H₂O (10 mls) were combined in a 20 mlmicrowave reactor and heated in the microwave at 150° C. for 7 minutes.The reaction was complete by LCMS (Sunfire, neutral). The mixture wasconcentrated, dissolved in NaOH (20 mls 0.5 N), filtered, extracted withether three times, and cooled to 0° C. At 0 ° C., 1.0 N HCl was addedslowly until a pH of 6.5 was attained. The mixture was stirred at 0° C.for 30 minutes and the product was filtered, dried in air, treated withexcess 2.0 N HCl in ether, concentrated, then triturated with CH₂Cl₂ togive 1.12 g, 99% (95.5% purity). 385 mgs were purified via prep HPLC(Sunfire, TFA), concentrated, treated with excess 1.0 N HCl (aq.),concentrated to a small volume and lyophilized to afford 240 mgs of thecaptioned compound. M+1=527; ¹H NMR δ (CD₃OD) 7.86 (d, 2H), 7.64 (s,4H), 7.49 (d, 2H), 7.36 (m, 2H), 7.28 (m , 1H), 7.02 (m, 1H), 6.95 (s,1H), 6.75 (q, 1H), 4.26 (t, 1H), 3.32 (m, 1H), 3.21 (m, 1H).

6.39. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4-yl)phenyl)propanoicacid

Benzylmercaptan (0.14 g, 1.11 mmol) was treated with NaH (60% in mineraloil, 67 mg, 1.66 mmol) in dry THF (15 ml) for 30 minutes.2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mmol) was added and themixture was stirred overnight. The mixture was diluted withmethylenechloride, washed with water, then brine, dried over MgSO4, andconcentrated to give 0.11 g of 4-(benzylthio)-6-chloropyrimidin-2-amine.

4-(Benzylthio)-6-chloropyrimidin-2-amine (0.1 g, 0.397 mmol),L-p-boronophenylalanine (0.1 g, 0.477 mmol), Pd(PPh₃)₂Cl₂ (17 mg, 0.024mmol), Na₂CO₃ (93 mg, 0.874 mmol), MeCN (2.5 ml) and water (2.5 ml) wereheated at 150° C. for 5 minutes in a microwave. The mixture wasconcentrated and purified via prep HPLC to give 0.42 g of the titlecompound. M+1=381; ¹H NMR (CD₃OD) δ 7.8 (d, 2H), 7.37 (t, 4H), 7.23 (m,2H), 7.16 (m, 1H), 6.98 (s, 1H), 4.43 (s, 2H), 4.20 (t, 1H), 3.29 (m,1H), 3.13 (M, 1H).

6.40. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(naphthalen-2-ylmethylthio)pyrimidin-4-yl)phenyl)propanoicacid

2-Mercaptonapthalene (0.2 g, 1.148) was treated with NaH (60% in Mineraloil, 92 mg, 2.30 mmol) in dry THF (10 ml) for 30 minutes.2-Amino-4,6-dichloropyrimidine (0.21 g, 1.26 mmol) was added and themixture was stirred overnight. The mixture was diluted withmethylenechloride, washed with water, then brine, dried over MgSO4, andconcentratred to give 0.18 g4-chloro-6-(naphthalen-2-ylmethylthio)pyrimidin-2-amine.

4-Chloro-6-(naphthalen-2-ylmethylthio)pyrimidin-2-amine (0.1 g, 0.331mmol), L-p-boronophenylalanine (83 mg, 0.397 mmol), Pd(PPh₃)₂Cl₂ (14 mg,0.020 mmol), Na₂CO₃ (77 mg, 0.729 mmol), MeCN (2.5 ml) and water (2.5ml) were heated at 150° C. for 5 minutes in a microwave. The mixture wasconcentrated and purified via prep HPLC to give 57 mg of the titlecompound. M+1=431; ¹H NMR (CD₃OD) δ 7.85 (s, 1H), 7.79 (d, 2H), 7.72 (d,3H), 7.46 (dd, 1H), 7.35 (m, 4H), 6.95 (s, 1H), 4.58 (s, 2H), 4.17 (m,1H), 3.26 (m, 1H), 3.11 (m, 1H).

6.41. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid

3,5-Difluorophenyl-trifluoromethyl ketone was treated with NaBH₄ (0.18g, 4.76 mmol) in THF (5 ml) for 2 hours. The mixture was quenched withwater, extracted with methylene chloride (2×). The organics werecombined, filtered through silica gel and concentrated to give 0.46 g of1-(3,4-difluorophenyl)-2,2,2-trifluoroethanol.

1-(3,4-Difluorophenyl)-2,2,2-trifluoroethanol (0.1 g, 0.471 mmol) wastreated with NaH (60% in mineral oil, 38 mg, 0.943 mmol) in dry THF (3ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (77 mg, 0.471 mmol)was added and the mixture was stirred at 50° C. for 6 hours. The mixturewas quenched with water and extracted with methylenechloride (2×). Theorganics were combined, washed with water, then brine, dried over MgSO4,and concentrated to give 0.14 g of4-chloro-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-2-amine.

4-Chloro-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-amine(0.14 g, 0.421 mmol), L-p-boronophenylalanine (110 mg, 0.505 mmol),Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), Na₂CO₃ (98 mg, 0.926 mmol), MeCN (2.5ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in amicrowave. The mixture was concentrated and purified via prep HPLC togive 74 mg of the title compound. M+1=469; ¹H NMR (CD₃OD) δ 7.83 (d,2H), 7.47 (m, 1H), 7.38 (m, 4H), 7.28 (m, 1H), 4.21 (t, 1H), 3.29 (m,1H), 3.15 (m, 1H).

6.42. Synthesis of(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid

To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50mls) at 0° C. was added NaBH₄ (1.5 g, 39.52 mmol). The mixture waswarmed to room temperature and stirred for 1 hour. The reaction wascomplete by TLC (CH₂Cl₂). The mixture was quenched with H₂O, rotaryevaporated to remove most of the THF, and extracted 2 times with CH₂Cl₂.The organics were combined, washed with brine, concentrated to a smallvolume and filtered through a plug of silica gel. The silica was washedwith CH₂Cl₂ to elute the product, and the resulting solution wasconcentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol.Yield: 92%.

1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol),m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs,0.0157 mmol Pd), K₂CO₃ (0.22 g, 1.576 mmol), EtOH (3 mls), and H₂O (0.5mls) were combined and heated at 80° C. for 4 hours. The reaction wasshown complete by TLC (CH₂Cl₂). The mixture was cooled, filtered,concentrated, slurried in CH₂Cl₂, and chromatographed over silica gel(CH₂Cl₂) to give 0.1 g of2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.

Alternatively, 1-(4-bromophenyl)-2,2,2-trifluoroethanol (0.98 g, 3.86mmol), m-tolylboronic acid (0.63 g, 4.63 mmol), Pd(PPh₃)₂Cl₂ (0.16 g,0.232 mmol Pd), Na₂CO₃ (0.90 g, 8.49 mmol), AcCN (10 mls), and H₂O (10mls) were combined and heated in the microwave at 150° C. for 10minutes. The reaction was shown complete by TLC (CH₂Cl₂). The mixturewas cooled, concentrated, slurried in CH₂Cl₂, filtered, andchromatographed over silica gel (CH₂Cl₂) to give 0.80 g of2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 79%.

Alternatively, tetrabutylammoniumfluoride (TBAF 1.0 N in THF 13 uL, 3.3mg, 0.013 mmol) was added to a mixture of3-methyl-biphenyl-2-carboxaldehyde (0.25 g, 1.27 mmol) andtrifluoromethytrimethyl silane (0.25 g, 1.53 mmol), in THF (1.5 ml) at0° C. The reaction was warmed to room temperature and stirred for 4hours. HCl (3.0 N, 2.0 ml) was added, and the mixture was stirred for 3hours. The mixture was concentrated, dissolved in methylene chloride,filtered through silica gel, and concentrated to give 0.15 g of2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol.

2,2,2-Trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol (0.15 g, 0.563 mmol)was treated with NaH (60% in mineral oil, 45 mg, 1.12 mmol) in dry THF(5 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (92 mg, 0.5633mmol) was added and the mixture was stirred at 50° C. for 6 hours. Themixture was quenched with water and extracted with methylenechloride(2×). The organics were combined, washed with water, then brine, driedover MgSO4, and concentrated to give 0.16 g of4-chloro-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine.

4-Chloro-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine(0.16 g, 0.406 mmol), L-p-boronophenylalanine (10 mg, 0.487 mmol),Pd(PPh₃)₂Cl₂ (17 mg, 0.024 mmol), Na₂CO₃ (95 mg, 0.894 mmol), MeCN (2.5ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in amicrowave. The mixture was concentrated and purified via prep HPLC togive 105 mg of the title compound. M+1=523; ¹H NMR (CD₃OD) δ 7.85 (d,2H), 7.70 (d, 1H), 7.44 (m, 4H), 7.31 (t, 1H), 7.21 (m, 2H), 7.10 (m,2H), 6.87 (q, 1H), 6.84 (s, 1H), 4.25 (t, 1H), 3.30 (m, 1H), 3.18 (m,1H).

6.43. Synthesis of(S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyridin-3-yl)phenyl)propanoicacid

Sodium triacetoxyl-borohydride (245 mg, 1.16 mmol) was added to thesolution of 5-bromo-pyridine-3-amine (100 mg, 0.57 mmol) and3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mmol) in 10 ml of1,2-dicloroethtane (DCE), of HOAc (66 μL, 2 eq. 1.16 mmol) was added,the mixture was stirred overnight at room temperature, followed byaddition of 15 ml of DCE. The organic phase was washed with water, anddried over sodium sulfate. The solvent was removed by under reducedpressure to give 200 mg of crude5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine, which wasused for the next step without further purification.

An Emrys process vial (2-5 ml) for microwave was charged with5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine (40 mg,0.106 mmol), 4-borono-L-phenylalanine (22 mg, 0.106 mmol) and 2 ml ofacetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to abovesolution followed by 10 mol percent ofdichlorobis(triphenylphosphine)-palladium (II). The reaction vessel wassealed and heated to 180° C. for 10 minutes with a microwave. Aftercooling, the reaction mixture was evaporated to dryness. The residue wasdissolved in 2.5 ml of methanol and purified with Prep-LC to give 20 mgof(S)-2-amino-3-(4-(5-3-(cyclophentyloxy-4-methoxy-benzylamino)pyridine-3-yl)phenyl)-propanoicacid. NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.59 (m, 2H), 1.7 (m, 6H), 3.17(m, 1H), 3.3 (m, 1H), 3.75 (s, 3H), 4.2 (dd, 1H) 4.39 (s, 2H), 4.7 (m,1H), 6.9 (m, 3H), 7.4 (d, 2H), 7.6 (d, 2H), 7.7 (s, 1H), 7.9 (s, 1H),8.15 (s, 1H); Analytical HPLC: RT 2.69; M+1: 462 (RT: 1.285).

6.44. Synthesis of2-Amino-3-(3-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

To a solution of tert-butyl 2-(diphenyhnethylene-amino)acetate (400 mg,1.35 mmol) in THF (25 ml) was added a solution of LDA (1.8M in THF, 2eq, 2.7 mmol, fresh bottle from Aldrich) over 5 minutes at −78° C., andthe resulting mixture was stirred for 20 minutes. A solution of2-(3-(bromomethyl)phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (460 mg, 1.2eq. 1.62 mmol) in THF (10 ml) was added drop-wise to the reactionmixture over 5 minutes. The reaction was continued at same (−78° C.)temperature for 30 minutes, and left for 3 hours at room temperature.The reaction was quenched with saturated NH₄Cl, followed by the additionof water (30 ml), and was extracted with EtOAc (2×40 ml). The organicfractions were combined and dried over Na₂SO₄. The solvent was thenconcentrated at reduced pressure and crudetert-Butyl-3-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)2(diphenylmethyleneamino)propionate was purified by column chromatography to provide theproduct as a semi-solid.

An Emrys process vial (20 ml) for microwave was charged with(R)-6-chloro-N²-(1-(naphthalene-2-yl)ethyl)-1,3,5-triazine-2,4-diamine(100 mg, 0.33 mmol),tert-butyl-3-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-2-(diphenylmethyleneamino)propanoate (248 mg, 0.5 mmol, 1.5 eq.) and 6 ml ofacetonitrile plus 6 ml of aqueous sodium carbonate (1M) was added toabove solution followed by 10 mol percent ofdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 190° C. for 10 minutes with microwave. Aftercooling, the reaction mixture was evaporated to dryness. The residue wasdissolved in 10 ml of THF, to which was added 5N.HCl (5 ml). The mixturewas refluxed for 2 hours in order to deprotect the benzophone andtert-butyl groups. The resulting reaction mixture was concentrated anddissolved in methanol (8 ml) and purified with Prep-LC to afford 15 mgof2-amino-3-(4(4-amino-6-((R)-1-(naphthalene-2-yl)ethylamino)-1,3,5-trizin-2-yl)phenyl)propanoicacid. NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.85 (d, 3H), 3.2-3.45 (m, 2H),4.37 (m, 1H), 5.5 (m, 1H), 7.4 (m, 1H), 7.6 (m 4H), 7.9 (m, 4H), 8.18(m, 2H), Analytical HPLC: RT 2.79 M+1: 429 (RT: 1.35).

6.45. Synthesis of2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)-2-fluorophenyl)propanoicacid

To a solution of tert-butyl 2-(diphenylmethylene-amino)acetate (1.1 g,3.73 mmol) in THF (30 ml) was added a solution of LDA (1.8M in THF, 1eq, 3.73 mmol, fresh bottle from Aldrich) over 5 minutes at −78° C., andthe resulting mixture was stirred for 20 minutes. A solution of4-bromo-1-(bromomethyl)-2-fluorobenezene (1 g, 3.74 mmol) in THF (10 ml)was added drop-wise to the reaction mixture over 5 minutes. The reactionwas continued at −78° C. for 30 minutes, after which it was left at roomtemperature for 3 hours. The reaction was quenched with saturated NH₄Cl,after which water (30 ml) was added. Product was extracted with EtOAc(2×40 ml), and the organic fractions were combined and dried overNa₂SO₄. The solvent was concentrated at reduced pressure and crudetert-Butyl3-(4-bromo-2-fluorophenyl)-2-(diphenylmethyleneamino)-propanoate Waspurified by column chromatography. The product was obtained as a solid.

An Emrys process vial (20 ml) for microwave was charged with tert-butyl3-(4-bromo-2-fluorophenyl)-2-(diphenylmethylene-amino)propanoate (600mg, 1.24 mmol), Pd(dba)2 (71 mg, 0.124 mmol), PCy3 (35 mg, 0.124 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (346 mg, 1.1eq. 1.36 mmol) and KOAc (182 mg, 1.5 eq., 1.86 mmol) 20 ml of DMF. Thereaction vessel was sealed and heated to 160° C. for 20 minutes bymicrowave. After cooling, the reaction mixture was evaporated to drynessunder reduced pressure. The residue was dissolved in H₂O (30 ml),extracted with EtOAc (2×40 ml), and purified with Prep-LC to give 220 mgof tert-butyl2-(diphenylmethyleneamino)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate.

An Emrys process vial (5 ml) for microwave was charged with(R)-6-chloro-N²-(1-(naphthalene-2-yl)ethyl)-1,3,5-triazine-2,4-diamine(67 mg, 0.22 mmol),tert-butyl-2-(diphenylmethyleneamino)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(120 mg, 0.22 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate(2 ml, 1M) was added to above solution followed by 10 mol percentdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 190° C. for 10 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 10 ml of THF, to which 5N.HCl (2 ml) was then added. Themixture was refluxed for 2 hours (deprotection of benzophone andtert-butyl groups). After deprotection of two groups, the mixture wasconcentrated, dissolved in methanol (5 ml), and purified with Prep-LC toafford 10 mg of2-amino-3-(4-(4-amino-6-((R)-1-(naphthalene-2-yl)ethylamino)-1,3,5-trizin-2-yl)-2-fluorophenyl)propanoicacid. NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.6 (d, 3H), 3.07 (m, 1H), 3.45(m, 1H), 3.8 (m, 1H), 5.45 (m, 1H), 7.4 (m, 4H), 7.6 (m 1H), 7.8 (m,4H), 8.08 (m, 1H), Analytical HPLC: RT 2.88, M+1: 447 (RT: 1.44).

6.46. Synthesis of(2S)-2-Amino-3-(4-(4-amino-6-(1-(adamantyll)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

A solution of adamantine amine (1 equivalent),2-amino-4,6-dichloro-[1,3,5]triazine (1 equivalent) and diisopropylethyl amine (5 equivalents, Aldrich) in anhydrous 1,4-dioxane wasrefluxed at 130° C. for 3 hours. After completion of the reaction, thedioxane was removed under reduced pressure. The reaction was then cooledto room temperature, water was added, and product was extracted withdichloromethane (2×40 ml). The combined organic solution was dried overNa₂SO₄ and concentrated to afford product, which was used in the nextstep without purification.

An Emrys process vial (20 ml) for microwave was charged with adamantinetrizine chloride (200 mg, 0.65 mmol), 4-borono-L-phenylalanine (135 mg,0.65 mmol) and 5 ml of acetonitrile. Aqueous sodium carbonate (5 ml, 1M)was added to above solution followed by 5 mol percentdichlorobis(triphenylphosphine)-palladium(II). The reaction vessel wassealed and heated to 190° C. for 20 minutes by microwave. After cooling,the reaction mixture was evaporated to dryness. The residue wasdissolved in 4 ml of methanol and purified with Prep-LC to give 60 mg(yield 21%) of coupled product. NMR: ¹H-NMR (400 MHz, CD₃OD): δ 1.22 (m,3H), 1.6-1-8 (m, 12H), 2.01 (d, 3H), 3.25-3.42 (m, 2H), 4.0 (m, 1H),4.40 (m, 1H), 7.6 (d, 2H), 8.2 (d, 2H), Analytical HPLC: RT 3.11, M+1:437 (RT: 1.76).

6.47. Alternative Synthesis of(2S)-2-Amino-3-(4-(4-amino-6-(1-(adamantyll)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid

Adamantane (2-yl) ethyl cyanoguanidine was prepared by forming asolution of cyanoguanidine (1 equivalent),(S)-2-amino-3-(4-cyanophenylpropanoic acid (1 equivalent) and potassiumtertiary butaoxide (3.5 equivalent, Aldrich) in dry n-BuOH, which wasvigorously refluxed at 160° C. in a sealed tube for 2 days. Aftercompletion of the reaction, the mixture was allowed to cool to roomtemperature, and the reaction was quenched with water. Solvent wasremoved under reduced pressure. Again, after allowing to cool to roomtemperature, the reaction mixture was brought to pH 12-14 by adding 1NNaOH. Then, impurities were removed while extracting with Ether:EtOAc(9:1, 2×100 ml). The aqueous solution was cooled to 0° C., 1N HCl wasthen added to adjust pH to 7. The pale yellow product was slowly crashedout in H₂O, the mixture was kept in a refrigerator for 30 minutes, andthe solid was obtained by filtration with 92% purity. Compound wascrystallized from MeOH to afford a white solid (>98% pure, 48-78%yield). ¹H-NMR (400 MHz, CD₃OD): δ 1.0 (d, 3H), 1.45-1.6 (m, 6H),4.62-4.8 (m, 4H) 2.0 (m, 2H), 3.3 (m, 1H), 3.5 (m, 1H); Analytical HPLC:RT 2.69; M+1: 462 (RT: 1.285).

The title compound was prepared from adamantane (2-yl) ethylcyanoguanidine using the method shown in Scheme 6.

6.48. Synthesis of(S)-2-Amino-3-(4-(5-fluoro-4-((R)-1-(naphthalen-2-yl)ethylamino)pyrimidin-2-yl)phenyl)propanoicacid

A mixture of (R)-(+)-1-(2-napthyl)ethylamine (102.6 mg, 0.599 mmol),2,4-dichloro-5-fluroro pyrimidine (100 mg, 0.599 mmol) and cesiumcarbonate (390 mg, 1.2 mmol) was dissolved in 1,4-dioxane (3 ml) and H₂O(3 ml) in a 10 ml microwave vial. The mixture was stirred in themicrowave reactor at 80° C. for 10 minutes. The residue was dissolved inCH₂Cl₂ (50 ml), washed with water (20 ml), brine (20 ml) dried (Na₂SO₄)and concentrated to get the crude intermediate2-chloro-5-fluoro-pyrimidin-4-yl)-(1-naphthalen-2-yl-ethyl)-amine.

The crude intermediate (250 mg, 0.83 mmol) was then dissolved in 6.0 mlof MeCN and 6 ml of H₂O in a 20 ml microwave vial. To this solution wereadded L-p-borono-phenylalanine (173.6 mg, 0.83 mmol), sodium carbonate(173.6 mg, 1.66 mmol) and catalytic amount ofdichlorobis(triphenylphosphine)-palladium(II) (11.6 mg, 0.0166 mmol).The reaction vial was then sealed and stirred in the microwave reactorat 150° C. for 7 minutes. The contents were then filtered, and thefiltrate was concentrated and dissolved in MeOH and H₂O (1:1) andpurified by preparative HPLC using MeOH/H₂O/TFA as the solvent system.The combined pure fraction were evaporated in vacuo and further dried ona lyophilizer to give 154 mg of2-amino-3-{4-[5-fluoro-4-(1-naphthalen-2-yl-ethylamino)-pryrimidin-2-yl]-phenyl}-propionicacid. NMR: ¹H-NMR (400 MHz, CD₃OD) δ 1.8 (d, 3H) 3.2-3.4 (m, 2H), 4.35(m, 1H), 5.7 (q, 1H), 7.5 (m, 4H), 7.6 (d, 1H), 7.8-7.9 (m, 4H), 8.1 (d,2H), 8.3 (d, 1H). LCMS:M+1=431.

6.49. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(4-(trifluoromethyl)-benzylamino)pyrimidin-4-yl)phenyl)propanoicacid

A mixture of trifluoromethyl benzylamine (106.8 mg, 0.610 mmol),2-amino-4,6-dichloropyrimidine (100 mg, 0.610 mmol) and cesium carbonate(217 mg, 1.2 mmol) was dissolved in 1,4-dioxane (6 ml) and H₂O (6 ml) ina 20 ml microwave vial. The mixture was stirred in the microwave reactorat 210° C. for 25 minutes. The solvent was then removed. The residue wasdissolved in CH₂Cl₂ (50 ml), washed with water (20 ml), brine (20 ml),dried (Na₂SO₄) and concentrated to get the crude intermediate6-chloro-N-4′-(trifluoromethyl-benzyl)-pryrimidine-2-4-diamine.

The crude intermediate (150 mg, 0.497 mmol) was then dissolved in 3.0 mlof MeCN and 3 ml of H₂O in a 10 ml microwave vial. To this solution wereadded L-p-borono-phenylalanine (104 mg, 0.497 mmol), sodium carbonate(150 mg, 0.994 mmol) and catalytic amount ofdichlorobis(triphenylphosphine)-palladium(II) (6.9 mg, 0.00994 mmol).The reaction vial was then sealed and stirred in the microwave reactorat 150° C. for 5 minutes. The contents were filtered, and the filtratewas concentrated and dissolved in MeOH and H₂O (1:1) and purified bypreparative HPLC using a MeOH/H₂O/TFA solvent system. The combined purefractions were evaporated in vacuo and further dried on a lyophilizer toafford2-amino-3-{4-[2-amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-phenyl}-propionicacid. NMR: ¹H-NMR (300 MHz, CD₃OD) δ 3.1-3.3 (m, 2H), 4.2 (t, 1H), 4.7(s, 2H), 6.3 (s, 1H), 7.4-7.5 (m, 4H), 7.6 (d, 2H), 7.7 (d, 2H). LCMS:M+1=432.

6.50. Synthesis of2-Amino-3-(5-(5-phenylthiophen-2-yl)-1H-indol-3-yl)propanoic acid

2-Amino-3-(5-bromo-1H-indol-3-yl)-propionic acid (0.020 g, 0.071 mmol)was added to a 5 ml microwave vial, which contained5-phenyl-thiophen-2-boronic acid (0.016 g, 0.078 mmol), Na₂CO₃ (0.015 g,0.142 mmol), acetonitrile (1.5 ml)/water (1.5 ml) anddichlorobis(triphenylphosphine)-palladium (3 mg, 0.003 mmol). Microwavevial was capped and stirred at 150° C. for 5 min under microwaveradiation. Reaction mixture was cooled, filtered through a syringefilter and then separated by a reverse phase preparative-HPLC usingYMC-Pack ODS 100×30 mm ID column (MeOH/H₂O/TFA solvent system). The purefractions were concentrated in vacuum. The product was then suspended in5 ml of water, frozen and lyophilized to give 5 mg of pure product,2-amino-3-[5-(5-phenyl-thiophen-2-yl)-1H-indol-3-yl]-propionic acid.1H-NMR (300 MHz, CD₃OD): 3.21-3.26 (m, 2H), 4.25 (q, 1H), 7.15-7.35 (m,8H), 7.58 (d, 2H), 7.82 (d, 1H).

6.51. Synthesis of(S)-2-Amino-3-(4-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid

A mixture of 1-ethynyl-4-phenoxy-benzene (126 mg, 0.65 mmol) and(S)-3-(4-azido-phenyl)-2-tert-butoxycarbonylamino-propionic acid (200mg, 0.65 mg) in H₂O:dioxane (5:1) was heated at 100° C. in a sealed tubefor overnight. After completion of reaction, 3N HCl (5 ml) was added andthe mixture was stirred for 2 hr at 50° C. Removal of solvent gave crudeproduct which was dissolved in MeOH and purified by preparative HPLC togive 45 mg of desired product (yield: 29%). ¹H-NMR (400 MHz, CD₃OD): δ(ppm) 3.2 (m, 1H), 3.4 (m, 1H), 4.3 (m, 1H), 6.9 (d, 2H), 7.0 (d, 2H),7.2 (m, 1H), 7.3 (d, 2H), 7.4-7.55 (m, 6H), 8.0 (s, 1H).

6.52. Synthesis of(S)-2-Amino-3-(4-(4-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid and(S)-2-Amino-3-(4-(5-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid

A mixture of thiophene-2-carboxylic acid (4-ethyl-phenyl) amide (117 mg,0.49 mmol) and(S)-3-(4-azido-phenyl)-2-tert-butoxycarbonylamino-propionic acid (150mg, 0.49 mg) in 5 ml of H₂O:dioxane (5:1) was heated at 100° C. in asealed tube overnight. After completion of reaction, 3N HCl (5 ml) wasadded and the mixture was stirred for 2 hr at 50° C. Removal of solventgave crude product which was dissolved in MeOH and purified bypreparative HPLC. According to LCMS (retention time) and NMR, tworegio-isomers were obtained (total yield: 70 mg, 66%). The major productis(S)-2-amino-3-(4-(4-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid. NMR: ¹H-NMR (400 MHz, CD₃OD): δ 3.2 (m, 1H), 3.4 (m, 1H), 4.3 (m,1H), 7.15 (m, 1H), 7.3 (d, 2H), 7.6 (m, 4H), 7.0 (m, 3H), 7.95 (d, 1H),8.0 (s, 1H). The minor product is(S)-2-amino-3-(4-(5-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid. ¹H-NMR (400 MHz, CD3OD): δ 3.2 (m, 1H), 3.4 (m, 1H), 4.35 (m, 1H),7.2 (m, 1H), 7.3 (d, 2H), 7.5-7.6 (m, 4H), 7.75 (m, 3H), 7.95 (d, 1H),8.05 (s, 1H).

6.53. Synthesis of(S)-2-Amino-3-(4-(2-amino-6-(phenylethynyl)pyrimidin-4-yl)phenyl)propanoicacid

2-Amino 4,6-dichloro pyrimidine (0.180 g, 1.1 mmol),trimethyl-phenylethynyl-stannane (0.264 g, 1 mmol), were dissolved inTHF (20 ml) and the mixture was stirred at 65° C. for 12 h. LCMSindicated the completion of reaction. Solvent was removed and theresidue was directly used in the following step.

The crude intermediate (0.42 g), L-p-borono-phenylalanine (0.210 g, 1mmol), sodium carbonate (0.210 g, 2 mmol), anddichlorobis(triphenylphosphine)-palladium(II) (25 mg, 0.036 mmol) weredissolved in a mixture of MeCN (3 ml) and H₂O (3 ml) in a 10 mlmicrowave vial. The vial was sealed and stirred in the microwave reactorat 150° C. for 6 min. The mixture was filtered and the filtrate wasconcentrated. Residue was purified by preparative HPLC usingMeOH/H₂O/TFA as solvent system to obtain(S)-2-amino-3-[4-(2-amino-6-phenylethynyl-pyrimidin-4-yl(-phenyl]-propionicacid as a TFA salt. ¹H-NMR (400 MHz, CD₃OD): δ (ppm) 3.20-3.42 (m, 2H),4.31 (m, 1H), 7.40-7.51 (m, 6H), 7.62 (d, 2H), 8.18 (d, 2H).

6.54. Additional Compounds

Additional compounds prepared using methods known in the art and/ordescribed herein are listed below: LCMS HPLC Method Compound (M + 1)(Time (min)) (S)-2-amino-3-(4-(5-(2-fluoro-4,5- 426 C (3.04)dimethoxybenzylamino)pyrazin-2-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(4-(2-methoxyphenyl)piperidin-1- 448 I(3.03) yl)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(6-(3-(cyclopentyloxy)-4- 507 J (3.21)methoxybenzylamino)-2-(dimethylamino)pyrimidin-4- yl)phenyl)propanoicacid (S)-2-amino-3-(4-(5-(3,4-dimethylbenzylamino)pyrazin-2- 377 C(3.15) yl)phenyl)propanoic acid(S)-2-amino-3-(4-(5-(biphenyl-2-ylmethylamino)pyrazin-2- 425 D (4.00)yl)phenyl)propanoic acid (S)-ethyl 2-amino-3-(4-(2-amino-6-(4- 460 F(2.52) (trifluoromethyl)benzylamino)pyrimidin-4-yl)phenyl)propanoate(S)-2-amino-3-(4-(5-(cyclopentylmethylamino)pyrazin-2- 341 C (2.77)yl)phenyl)propanoic acid (2S)-2-amino-3-(4-(2-amino-6-(3-(2- 472 A(2.87) (trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1,2,3,4-tetrahydronaphthalen-1- 404 A(2.65) ylamino)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-1-(naphthalen-2- 429 A (2.73)yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1,2- 454 K (1.34)diphenylethylamino)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-(benzo[b]thiophen-3- 510 D (2.02)yl)phenyl)ethylamino)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(4-amino-6-((R)-1-(4′-methoxybiphenyl-4- 485 J (2.99)yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoic acid2-amino-3-(1-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)- 436 B(2.25) 1,3,5-triazin-2-yl)piperidin-4-yl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(1-(4-fluoronaphthalen-1- 447 H (1.68)yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(4-amino-6-((3′-fluorobiphenyl-4- 459 J (2.89)yl)methylamino)-1,3,5-triazin-2-yl)phenyl)propanoic acid2-amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)- 447 A(2.88) 1,3,5-triazin-2-yl)-2-fluorophenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- 539 M (3.83)methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′- 528 F (3.41)fluorobiphenyl-2-yl)ethoxy)-1,3,5-triazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(1-(4-tert- 435 J (1.82)butylphenyl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′- 527 D (2.09)fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(6,7-dihydroxy-1-methyl-3,4- 437 B (2.47)dihydroisoquinolin-2(1H)-yl)-1,3,5-triazin-2- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′- 524 D (2.22)methylbiphenyl-4-yl)ethoxy)-1,3,5-triazin-2- yl)phenyl)propanoic acid(S)-2-amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2- 428 A (2.90)yl)ethylamino)pyrimidin-2-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4- 379 E (1.66)yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′- 527 E (2.07)fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(3-(4-chlorophenoxy)piperidin-1- 453 A (2.67)yl)pyrimidin-4-yl)phenyl)propanoic acid(S)-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5- 486 J(2.83) triazin-2-yl)phenyl)-2-(2-aminoacetamido)propanoic acid(S)-2-amino-3-(4-(6-((R)-1-(naphthalen-2-yl)ethylamino)-2- 481 A (3.70)(trifluoromethyl)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(4-(3-chlorophenyl)piperazin-1- 453 L (0.72)yl)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1- 433 E (1.77)phenylethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1,4- 482 A (3.15)diphenylbutylamino)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(3′-chlorobiphenyl-2-yl)-2,2,2- 528 E (2.35)trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(4-amino-6-(1-(biphenyl-4-yl)-2,2,2- 510 D (2.14)trifluoroethoxy)-1,3,5-triazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,3,3,3-pentafluoro-1-(3- 515 N (3.34)fluoro-4-methylphenyl)propoxy)pyrimidin-4- yl)phenyl)propanoic acid(S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- 567 N(2.17) methoxybiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoate(S)-2-amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-1-(3′- 539 N (3.36)methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3-fluoro-3′- 557 O(3.52) methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(3′-(dimethylamino)biphenyl- 552 Q(3.00) 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy-5- 553 N(3.63) methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′-methoxy-5- 553 N(3.61) methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy-3- 617 O(3.28) (methylsulfonyl)biphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(cyclopropylmethoxy)-4- 521 N (1.57)fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(6-(1-(2-(cyclopropylmethoxy)-4- 507 N (1.62)fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2- 520 N (1.69)(isopentyloxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4- 512 —yl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′- 539 N (3.50)methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(3′-carbamoylbiphenyl-2-yl)- 552 N(3.14) 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4′-carbamoylbiphenyl-2-yl)- 552 N(3.05) 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(2- 555 N (1.55)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(2- 541 N (1.59)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(2- 505 N (1.74)(isopentyloxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-3-(4-(6-(1-(3′-acetamidobiphenyl-2-yl)-2,2,2- 566 N (3.18)trifluoroethoxy)-2-aminopyrimidin-4-yl)phenyl)-2- aminopropanoic acid(2S)-3-(4-(6-(1-(4′-acetamidobiphenyl-2-yl)-2,2,2- 566 N (3.23)trifluoroethoxy)-2-aminopyrimidin-4-yl)phenyl)-2- aminopropanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4-cyanophenyl)-2,2,2- 458 —trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-p- 475 —tolylethoxy)pyrimidin-4-yl)phenyl)propanoate(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1- 493 O (2.97)methoxybicyclo[2.2.2]oct-5-en-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4-(cyclopentyloxy)phenyl)- 517 N (1.61)2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(4-(cyclopentyloxy)phenyl)-2,2,2- 503 N (1.67)trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(3- 556 N (1.59)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4,5-dimethoxybiphenyl-2-yl)- 569 S(3.34) 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4,5-dimethoxy-3′- 583 S (3.50)methylbiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-1-(2′-methylbiphenyl-2- 508 —yl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(3- 541 N (1.64)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(3,5- 561 N (1.64)difluorophenoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(4- 556 N (1.58)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4′-((S)-2-amino-2- 596 —carboxyethyl)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-bromophenyl)-2,2,2- 513 —trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2- 508 —yl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4- 539 S (3.51)methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-1-(2-(4-methylthiophen-3- 514 —yl)phenyl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-methoxy-3′- 553 S(3.66) methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′- 539 —(hydroxymethyl)biphenyl-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(1-(3′-cyanobiphenyl-2-yl)-2,2,2- 534— trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(2-(3,5-difluorophenoxy)phenyl)-2,2,2- 547 N(1.69) trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(4- 541 N (1.63)methoxyphenoxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(4- 536 —methylthiazol-2-yl)thiophen-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5-(4- 530 O (3.14)methoxyphenyl)isoxazol-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-phenyl-5- 567 O(3.24) (trifluoromethyl)-1H-pyrazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(cyclohexyloxy)-4- 545 N (1.76)methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(1-(2-(cyclopentyloxy)-4- 532 N (1.71)methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(1-(benzo[d]thiazol-6-yl)-2,2,2- 490 O(2.66) trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-methyl-1H- 437 —imidazol-5-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(2-(cyclopentyloxy)-4-methylphenyl)- 517 N(1.78) 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(2-(cyclohexyloxy)-4-methylphenyl)- 531 N (1.87)2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(pyridin-3- 434 —yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(1,3-dimethyl-1H-pyrazol-5- 451 —yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(3-hydroxyphenyl)pyrimidin-4- 351 —yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′- 526 —hydroxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(3,5-difluorophenyl)pyrimidin-4- 371 —yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(3′,5′-difluorobiphenyl-2-yl)- 546 —2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-3- 512 —yl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(5-ethoxy-2-methyl-2,3- 533 O (3.16)dihydrobenzofuran-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(benzofuran-5-yl)-2,2,2- 473 —trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-m- 513 —tolylfuran-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid (S)-ethyl3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- 596 N (3.55)methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoate(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(2-(4-methylthiophen-3- 514 —yl)phenyl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5-methyl-3- 514 N(3.12) phenylisoxazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(3-(methylthio)phenyl)pyrimidin- 381 —4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′- 555 —(methylthio)biphenyl-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(3′- 566 —((dimethylamino)methyl)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(3- 419 —(trifluoromethoxy)phenyl)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′- 593 —(trifluoromethoxy)biphenyl-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoicacid (S)-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl- 596N (1.51) 4-yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-methyl-5- 513 N(2.88) phenyl-1H-pyrazol-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4- 511 —(methylsulfonyl)phenyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-1-(3′- 552 S (3.09)(dimethylamino)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid (2S)-2-amino-3-(4-(2-amino-6-(1-(2-chloro-4-545 — (methylsulfonyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3-(furan-2- 505 —yl)thiophen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(cyclopentyloxy)-4- 543 N (1.66)fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(3- 543 O (3.59)methoxyphenyl)cyclohex-1-enyl)ethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(pyrimidin-5- 435 —yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-methoxybiphenyl-3- 524 —yl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((S)-1-(3′- 552 N (3.08)(dimethylamino)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(furan-2- 542 N(2.61) carboxamido)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4-chloro-2- 545 —(methylsulfonyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid (S)-isopropyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1- 581 —(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoate(2S)-2-amino-3-(4-(6-(1-(2-(cyclopentyloxy)-4-fluorophenyl)- 520 N(1.73) 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(1-(2-(cyclohexyloxy)-4-fluorophenyl)- 534 N (1.81)2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-(thiophen-2- 521 O(3.36) yl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-(2,2,2-trifluoro-1-(3′-methoxybiphenyl-4- 529 Q(2.30) yl)ethoxy)thiazol-5-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(cyclohexyloxy)-4- 549 N (1.70)fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoicacid (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-(4- 545 O (3.41)methoxyphenyl)cyclohexyl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(4-fluoro-2- 450 N (1.50)methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-fluoro-2- 465 N(1.45) methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(oxazol-2- 432 O (1.76)yl(phenyl)methoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(1-cyclohexyl-2,2,2- 452 O (3.47)trifluoroethylideneaminooxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(2-(3- 543 N (3.02)(dimethylamino)phenyl)furan-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5- 515 N (3.39)phenylthiophen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-phenyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′- 615 Q(3.00) methoxybiphenyl-4-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoate(S)-2-amino-3-(4-(2-amino-6-((R)-1-(3′- 566 N (2.60)((dimethylamino)methyl)biphenyl-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(1-(3-methoxybenzoyl)-1H-pyrazol-4- 366 O (2.55)yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(5-phenylfuran-2- 484 N (3.65)yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4-chloro-2-fluorophenyl)- 486 N (3.14)2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S,E)-2-amino-3-(4-(2-amino-6-(4- 429 N (2.94)(trifluoromethyl)styryl)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(3,4-dichlorophenyl)-2,2,2- 502 N (3.31)trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-(4-chloro-3-fluorophenyl)- 486 N (3.13)2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-((R)-1-(3′- 552 N (2.66)(dimethylamino)biphenyl-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1-chloro-2,2,2-trifluoro-1-(4- 573 N(3.77) methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(6-(2,2,2-trifluoro-1-(5-phenylthiophen-2- 500 N(3.75) yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(5-(4-phenoxyphenyl)-1H-1,2,3-triazol-1- 401 O (3.20)yl)phenyl)propanoic acid (S,E)-2-amino-3-(4-(2-amino-6-(2-(biphenyl-4-437 N (3.17) yl)vinyl)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(4-amino-6-((R)-2,2,2-trifluoro-1-(3′- 539 —methoxybiphenyl-4-yl)ethoxy)pyrimidin-2-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(4′-methoxybiphenyl-4- 428 N (2.78)ylsulfonamido)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(3- 540 N (3.09)methoxyphenyl)pyridin-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(2-fluoro-3- 558 N(3.00) methoxyphenyl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid2-amino-3-(5-(4′-methylbiphenyl-4-yl)-1H-indol-3-yl)propanoic 371 N(1.48) acid 2-amino-3-(5-m-tolyl-1H-indol-3-yl)propanoic acid 295 N(1.19) (2S)-2-amino-3-(4-(2-(2-methoxyphenyl)furan-3- 358 O (2.68)carboxamido)phenyl)propanoic acid2-amino-3-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indol-3- 361 N (1.10)yl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(thiophen-2- 516 N(1.42) yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid2-amino-3-(6-(1-benzyl-1H-pyrazol-4-yl)-1H-indol-3- 361 N (1.09)yl)propanoic acid(S)-2-amino-3-(4-((2-(4-(trifluoromethyl)phenyl)thiazol-4- 422 O (3.00)yl)methylamino)phenyl)propanoic acid(S)-2-amino-3-(4-((4′-methoxybiphenyl-4- 441 O (2.94)ylsulfonamido)methyl)phenyl)propanoic acid(S)-2-amino-3-(4-(3-(2-methoxydibenzo[b,d]furan-3- 420 O (3.36)yl)ureido)phenyl)propanoic acid (S)-2-amino-3-(4-(3-(2,2- 404 O (2.97)diphenylethyl)ureido)phenyl)propanoic acid(S)-2-amino-3-(4-(phenylethynyl)phenyl)propanoic acid 266 N (2.91)(S)-2-amino-3-(4-(2-amino-6-((5-(1-methyl-S-(trifluoromethyl) 410 N(1.39) 1H-pyrazol-3-yl)thiophen-2-yl)methoxy)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(1,1,1-trifluoro-3-((R)-2,2,3- 479 O (3.42)trimethylcyclopent-3-enyl)propan-2-yloxy)pyrimidin-4-yl)phenyl)propanoic acid (2S)-2-amino-3-(4-(2-amino-6-(3-(2- 429 N(1.53) hydroxyethylcarbamoyl)piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoic acid(2S)-2-amino-3-(4-(2-amino-6-(3-(pyridin-2-yloxy)piperidin-1- 435 N(2.11) yl)pyrimidin-4-yl)phenyl)propanoic acid(S)-2-amino-3-(4-(2-amino-6-(4-chloro-3-(piperidine-1- 480 N (2.75)carbonyl)phenyl)pyrimidin-4-yl)phenyl)propanoic acid

6.55. In Vitro Inhibition Assays

Human TPH1, TPH2, tyrosine hydroxylase (TH) and phenylalaninehydroxylase (PH) were all generated using genes having the followingaccession numbers, respectively: X52836, AY098914, X05290, and U49897.

The full-length coding sequence of human TPH1 was cloned into thebacterial expression vector pET24 (Novagen, Madison, Wis., USA). Asingle colony of BL21(DE3) cells harboring the expression vector wasinoculated into 50 ml of L broth (LB)-kanamycin media and grown up at37° C. overnight with shaking. Half of the culture (25 ml) was thentransferred into 3 L of media containing 1.5% yeast extract, 2% BactoPeptone, 0.1 mM tryptophan, 0.1 mM ferrous ammonium sulfate, and 50 mMphosphate buffer (pH 7.0), and grown to OD₆₀₀=6 at 37° C. with oxygensupplemented at 40%, pH maintained at 7.0, and glucose added. Expressionof TPH1 was induced with 15% D-lactose over a period of 10 hours at 25°C. The cells were spun down and washed once with phosphate bufferedsaline (PBS).

TPH1 was purified by affinity chromatography based on its binding topterin. The cell pellet was resuspended in a lysis buffer (100 ml/20 g)containing 50 mM Tris-Cl, pH 7.6, 0.5 M NaCl, 0.1% Tween-20, 2 mM EDTA,5 mM DTT, protease inhibitor mixture (Roche Applied Science,Indianapolis, Ind., USA) and 1 mM phenylmethanesulfonyl fluoride (PMSF),and the cells were lyzed with a microfluidizer. The lysate wascentrifuged and the supernatant was loaded onto a pterin-coupledsepharose 4B column that was equilibrated with a buffer containing 50 mMTris, pH 8.0, 2 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, and 2 mM DTT. Thecolumn was washed with 50 ml of this buffer and TPH1 was eluded with abuffer containing 30 mM NaHCO₃, pH 10.5, 0.5 M NaCl, 0.1% Tween-20, 0.5mM EDTA, 2 mM DTT, and 10% glycerol. Eluted enzyme was immediatelyneutralized with 200 mM KH₂PO₄, pH 7.0, 0.5 M NaCl, 20 mM DTT, 0.5 mMEDTA, and 10% glycerol, and stored at −80° C.

Human tryptophan hydroxylase type II (TPH2), tyrosine hydroxylase (TH)and phenylalanine hydroxylase (PAH) were expressed and purifiedessentially in the same way, except the cells were supplemented withtyrosine for TH and phenylalanine for PAH during growth.

TPH1 and TPH2 activities were measured in a reaction mixture containing50 mM 4-morpholinepropanesulfonic acid (MOPS), pH 7.0, 60 μM tryptophan,100 mM ammonium sulfate, 100 μM ferrous ammonium sulfate, 0.5 mMtris(2-carboxyethyl)phosphine (TCEP), 0.3 mM 6-methyl tetrahydropterin,0.05 mg/ml catalase, and 0.9 mM DTT. The reactions were initiated byadding TPH1 to a final concentration of 7.5 nM. Initial velocity of thereactions was determined by following the change of fluorescence at 360nm (excitation wavelength=300 nm). TPH1 and TPH2 inhibition wasdetermined by measuring their activities at various compoundconcentrations, and the potency of a given compound was calculated usingthe equation:$v = {b + \frac{v_{0} - b}{1 + \left( \frac{\lbrack C\rbrack}{\left\lbrack I_{c\quad 50} \right\rbrack} \right)^{D}}}$where v is the initial velocity at a given compound concentration C, v₀is the v when C=0, b is the background signal, D is the Hill slope whichis approximately equal to 1, and I_(c50) is the concentration of thecompound that inhibits half of the maximum enzyme activity.

Human TH and PAH activities were determined by measuring the amount of³H₂O generated using L-[3,4-³H]-tyrosine and L-[4-³H]-phenylalanine,respectively. The enzyme (100 nM) was first incubated with its substrateat 0.1 mM for about 10 minutes, and added to a reaction mixturecontaining 50 mM MOPS, pH 7.2, 100 mM ammonium sulfate, 0.05% Tween-20,1.5 mM TCEP, 100 μM ferrous ammonium sulfate, 0.1 mM tyrosine orphenylalanine, 0.2 mM 6-methyl tetrahydropterin, 0.05 mg/ml of catalase,and 2 mM DTT. The reactions were allowed to proceed for 10-15 minutesand stopped by the addition of 2 M HCl. The mixtures were then filteredthrough activated charcoal and the radioactivity in the filtrate wasdetermined by scintillation counting. Activities of of compounds on THand PAH were determined using this assay and calculated in the same wayas on TPH1 and TPH2.

6.56. Cell-Based Inhibition Assays

Two types of cell lines were used for screening: RBL2H3 is a ratmastocytoma cell line, which contains TPH1 and makes5-hydroxytrypotamine (5HT) spontaneously; BON is a human carcinoid cellline, which contains TPH1 and makes 5-hydroxytryptophan (5HTP). The CBAswere performed in 96-well plate format. The mobile phase used in HPLCcontained 97% of 100 mM sodium acetate, pH 3.5 and 3% acetonitrile. AWaters C18 column (4.6×50 mm) was used with Waters HPLC (model 2795). Amulti-channel fluorometer (model 2475) was used to monitor the flowthrough by setting at 280 nm as the excitation wavelength and 360 nm asthe emission wavelength.

RBL CBA: Cells were grown in complete media (containing 5% bovine serum)for 3-4 hours to allow cells to attach to plate wells (7K cell/well).Compounds were then added to each well in the concentration range of0.016 μM to 11.36 μM. The controls were cells in complete media withoutany compound present. Cells were harvested after 3 days of incubation at37° C. Cells were >95% confluent without compound present. Media wereremoved from plate and cells were lysed with equal volume of 0.1 N NaOH.A large portion of the cell lysate was treated by mixing with equalvolume of 1M TCA and then filtered through glass fiber. The filtrateswere loaded on reverse phase HPLC for analyzing 5HT concentrations. Asmall portion of the cell lysate was also taken to measure proteinconcentration of the cells that reflects the cytotoxicity of thecompounds at the concentration used. The protein concentration wasmeasured by using BCA method.

The average of 5HT level in cells without compound treated was used asthe maximum value in the IC₅₀ derivation according to the equationprovided above. The minimum value of 5HT is either set at 0 or fromcells that treated with the highest concentration of compound if acompound is not cytotoxic at that concentration.

BON CBA: Cells were grown in equal volume of DMEM and F12K with 5%bovine serum for 3-4 hours (20K cell/well) and compound was added at aconcentration range of 0.07 μM to 50 μM. The cells were incubated at 37°C. overnight. Fifty μM of the culture supernatant was then taken for5HTP measurement. The supernatant was mixed with equal volume of 1M TCA,then filtered through glass fiber. The filtrate was loaded on reversephase HPLC for 5HTP concentration measurement. The cell viability wasmeasured by treating the remaining cells with Promega Celltiter-GloLuminescent Cell Viability Assay. The compound potency was thencalculated in the same way as in the RBL CBA.

6.57. In Vivo Effects

The in vivo effects of a potent TPH 1 inhibitor of the invention wereevaluated in several studies by determining the change of 5-HT levels inthe intestines and brains of mice following oral administration of thecompound.

The compound was formulated in different vehicles to provide either asuspension or solution. Generally, 14-week-old male C57 albino mice weredosed once daily by oral gavage at 5 ml/kg for four consecutive days.Five hours after the last dose, the animals were quickly sacrificed.Various regions of the intestinal tract and whole brain were taken andfrozen immediately. 5-HT was extracted from the tissues and measured byHPLC. Blood samples were taken for exposure analysis.

The potent TPH1 inhibitor was found to reduce 5-HT levels in both thesmall and large intestine, but not in the brain. In one study, thecompound was formulated in H₂O and administered to mice at fourdifferent dose levels: 15, 50, 150, and 500 mg/kg, once daily by oralgavage. As shown in FIG.1, the compound caused significant reduction of5-HT in the jejunum and ileum in a dose-dependent fashion. In the colon,statistically significant reduction of 5-HT was seen at the 50, 150, and500 mg/kg/day dose levels. No significant change of 5-HT levels wasobserved in the brain at any of the dose levels.

1-2. (canceled)
 3. A potent TPH1 inhibitor of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; D is optionally substituted aryl orheterocycle; E is optionally substituted aryl or heterocycle; R₁ ishydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle,aryl, or heterocycle; R₂ is hydrogen or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R₃ is hydrogen,alkoxy, amino, cyano, halogen, hydroxyl, or optionally substitutedalkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, oroptionally substituted alkyl or aryl; R₅ is hydrogen or optionallysubstituted alkyl or aryl; and n is 0-3. 4-18. (canceled)
 19. The potentTPH1 inhibitor of claim 3, which is of the formula:

wherein: each of A₁ and A₂ is independently a monocyclic optionallysubstituted cycloalkyl, aryl, or heterocycle. 20-126. (canceled)
 127. Acompound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; E is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₃ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and q is1-2.
 128. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; E is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₃ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and q is1-2.
 129. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; E is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₃ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and r is1-3.
 130. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; E is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and eachR₁₀ is independently amino, cyano, halogen, hydrogen, OR₁₁, SR₁₁,NR₁₂R₁₃, or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₁ is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R₁₂ isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R₁₃ is independently hydrogen or optionallysubstituted alkyl alkyl-aryl or alkyl-heterocycle; and n is 0-3.131-157. (canceled)
 158. The compound of one of claims 127-130, whereinX is a bond or S.
 159. The compound of one of claims 127-130, wherein Xis —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, or —C≡C—.
 160. (canceled)161. The compound of one of claims 127-130, wherein X is —O—,—C(R₃R₄)O—, or —OC(R₃R₄)—.
 162. (canceled)
 163. (canceled)
 164. Thecompound of one of claims 127-130, wherein X is —S(O₂)—, —S(O₂)N(R₅)—,—N(R₅)S(O₂)—, —C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—.
 165. (canceled) 166.The compound of one of claims 127-130, wherein X is —N(R₅)—,—N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, or —N(R₅)C(R₃R₄)—. 167-175. (canceled)176. A compound, or a pharmaceutically acceptable salt or solvatethereof, wherein the compound is:(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((4′-methylbiphenyl-4-yl)methylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-morpholino-6-(naphthalen-2-ylmethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(trifluoromethyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-p-tolylethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-cyclohexyl-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(6-(2-fluorophenoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-(3-(4-chlorophenyl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-phenylethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(5-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)pyridin-2-yl)propanoicacid;(S)-2-Amino-3-(3-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)propanoicacid;(S)-2-Amino-3-(4′-(3-(cyclopentyloxy)-4-methoxybenzylamino)biphenyl-4-yl)propanoicacid;(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-((4′-methylbiphenyl-2-yl)methylamino)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-phenylethoxy)-pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)-pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-((3-(cyclopentyloxy)-4-methoxybenzyl)-(methyl)amino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-((1,3-dimethyl-1H-pyrazol-4-yl)methylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((S)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yloxy)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(biphenyl-2-yl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(1-(6,8-difluoronaphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(3,4-dimethoxyphenylcarbamoyl)-pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(4-(2-(trifluoromethyl)phenyl)-piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(methyl((R)-1-(naphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(biphenyl-4-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid; (S)-2-Morpholinoethyl2-amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoate;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(naphthalen-2-ylmethylthio)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyridin-3-yl)phenyl)propanoicacid;2-Amino-3-(3-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)-2-fluorophenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(1-(adamantyll)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-fluoro-4-((R)-1-(naphthalen-2-yl)ethylamino)pyrimidin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(4-(trifluoromethyl)-benzylamino)pyrimidin-4-yl)phenyl)propanoicacid; 2-amino-3-(5-(5-phenylthiophen-2-yl)-1H-indol-3-yl)propanoic acid;(S)-2-amino-3-(4-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid;(S)-2-amino-3-(4-(4-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid;(S)-2-amino-3-(4-(5-(4-(thiophene-2-carboxamido)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid;(S)-2-amino-3-(4-(2-amino-6-(phenylethynyl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(2-fluoro-4,5-dimethoxybenzylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(4-(2-methoxyphenyl)piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)-2-(dimethylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(3,4-dimethylbenzylamino)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(biphenyl-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoicacid; (S)-Ethyl2-amino-3-(4-(2-amino-6-(4-(trifluoromethyl)benzylamino)pyrimidin-4-yl)phenyl)propanoate;(S)-2-Amino-3-(4-(5-(cyclopentylmethylamino)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(3-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(naphthalen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1,2-diphenylethylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(4-(benzo[b]thiophen-3-yl)phenyl)ethylamino)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(4′-methoxybiphenyl-4-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;2-Amino-3-(1-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)piperidin-4-yl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(1-(4-fluoronaphthalen-1-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid; (S)-2-Amino-3-(4-(4-amino-6-((3′-fluorobiphenyl-4-yl)methylamino)-1,3,5-triazin-2-yl)phenyl)propanoic acid;2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)-2-fluorophenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-2-yl)ethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(1-(4-tert-butylphenyl)ethylamino)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(6,7-dihydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-4-yl)ethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((R)-1-(naphthalen-2-yl)ethylamino)pyrimidin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(3-(4-chlorophenoxy)piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-3-(4-(4-Amino-6-((R)-1-(naphthalen-2-yl)ethylamino)-1,3,5-triazin-2-yl)phenyl)-2-(2-aminoacetamido)propanoicacid;(S)-2-Amino-3-(4-(6-((R)-1-(naphthalen-2-yl)ethylamino)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(4-(3-chlorophenyl)piperazin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-phenylethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1,4-diphenylbutylamino)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(3′-chlorobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(4-amino-6-(1-(biphenyl-4-yl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,3,3,3-pentafluoro-1-(3-fluoro-4-methylphenyl)propoxy)pyrimidin-4-yl)phenyl)propanoicacid; (S)-Ethyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;(S)-2-Amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3-fluoro-3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3′-(dimethylamino)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy-5-methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′-methoxy-5-methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy-3-(methylsulfonyl)biphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(isopentyloxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4′-methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3′-carbamoylbiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4′-carbamoylbiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(2-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(2-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(2-(isopentyloxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-3-(4-(6-(1-(3′-Acetamidobiphenyl-2-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)phenyl)-2-aminopropanoicacid;(2S)-3-(4-(6-(1-(4′-Acetamidobiphenyl-2-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)phenyl)-2-aminopropanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4-cyanophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid; (S)-Ethyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-p-tolylethoxy)pyrimidin-4-yl)phenyl)propanoate;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-methoxybicyclo[2.2.2]oct-5-en-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4-(cyclopentyloxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(4-(cyclopentyloxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(3-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4,5-dimethoxybiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4,5-dimethoxy-3′-methylbiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-1-(2′-methylbiphenyl-2-yl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(3-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(3,5-difluorophenoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(4-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4′-((S)-2-amino-2-carboxyethyl)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-1-(2-(4-methylthiophen-3-yl)phenyl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-methoxy-3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-(hydroxymethyl)biphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3′-cyanobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(2-(3,5-difluorophenoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(4-(4-methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(4-methylthiazol-2-yl)thiophen-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5-(4-methoxyphenyl)isoxazol-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(benzo[d]thiazol-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-methyl-1H-imidazol-5-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(3-hydroxyphenyl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-hydroxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(3,5-difluorophenyl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3′,5′-difluorobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-3-yl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(5-ethoxy-2-methyl-2,3-dihydrobenzofuran-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(benzofuran-5-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-m-tolylfuran-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid; (S)-Ethyl3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoate;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(2-(4-methylthiophen-3-yl)phenyl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5-methyl-3-phenylisoxazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(3-(methylthio)phenyl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-(methylthio)biphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3′-((dimethylamino)methyl)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-(trifluoromethoxy)biphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-3-(4-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-methyl-5-phenyl-1H-pyrazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(3′-(dimethylamino)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-chloro-4-(methylsulfonyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3-(furan-2-yl)thiophen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(3-methoxyphenyl)cyclohex-1-enyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(pyrimidin-5-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-1-(3′-methoxybiphenyl-3-yl)ethoxy)pyrazin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((S)-1-(3′-(dimethylamino)biphenyl-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(2-(furan-2-carboxamido)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4-chloro-2-(methylsulfonyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid; (S)-Isopropyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;(2S)-2-Amino-3-(4-(6-(1-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(1-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-(thiophen-2-yl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-(2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)thiazol-5-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(1-(4-methoxyphenyl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(4-fluoro-2-methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(4-fluoro-2-methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(oxazol-2-yl(phenyl)methoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-(1-cyclohexyl-2,2,2-trifluoroethylideneaminooxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(2-(3-(dimethylamino)phenyl)furan-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(5-phenylthiophen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid; (S)-Phenyl2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(3′-((dimethylamino)methyl)biphenyl-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(1-(3-methoxybenzoyl)-1H-pyrazol-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(5-phenylfuran-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4-chloro-2-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S,E)-2-Amino-3-(4-(2-amino-6-(4-(trifluoromethyl)styryl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(2-amino-6-((R)-1-(3′-(dimethylamino)biphenyl-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1-chloro-2,2,2-trifluoro-1-(4-methoxybiphenyl-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-1-(5-phenylthiophen-2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(5-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)propanoicacid;(S,E)-2-Amino-3-(4-(2-amino-6-(2-(biphenyl-4-yl)vinyl)pyrimidin-4-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-2-yl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(4′-methoxybiphenyl-4-ylsulfonamido)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(3-methoxyphenyl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(2-fluoro-3-methoxyphenyl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid; 2-Amino-3-(5-(4′-methylbiphenyl-4-yl)-1H-indol-3-yl)propanoicacid; 2-Amino-3-(5-m-tolyl-1H-indol-3-yl)propanoic acid;(2S)-2-Amino-3-(4-(2-(2-methoxyphenyl)furan-3-carboxamido)phenyl)propanoicacid; 2-Amino-3-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indol-3-yl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(6-(thiophen-2-yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoicacid; 2-Amino-3-(6-(1-benzyl-1H-pyrazol-4-yl)-1H-indol-3-yl)propanoicacid;(S)-2-Amino-3-(4-((2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methylamino)phenyl)propanoicacid;(S)-2-Amino-3-(4-((4′-methoxybiphenyl-4-ylsulfonamido)methyl)phenyl)propanoicacid;(S)-2-Amino-3-(4-(3-(2-methoxydibenzo[b,d]furan-3-yl)ureido)phenyl)propanoicacid; (S)-2-Amino-3-(4-(3-(2,2-diphenylethyl)ureido)phenyl)propanoicacid; (S)-2-Amino-3-(4-(phenylethynyl)phenyl)propanoic acid;(S)-2-Amino-3-(4-(2-amino-6-((5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophen-2-yl)methoxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(1,1,1-trifluoro-3-((R)-2,2,3-trimethylcyclopent-3-enyl)propan-2-yloxy)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(3-(2-hydroxyethylcarbamoyl)piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid;(2S)-2-Amino-3-(4-(2-amino-6-(3-(pyridin-2-yloxy)piperidin-1-yl)pyrimidin-4-yl)phenyl)propanoicacid; or(S)-2-Amino-3-(4-(2-amino-6-(4-chloro-3-(piperidine-1-carbonyl)phenyl)pyrimidin-4-yl)phenyl)propanoicacid.
 177. The compound of claim 176, which is stereomerically pure.178. (canceled)
 179. (canceled)
 180. (canceled)
 181. A method ofinhibiting TPH1 activity, which comprises contacting TPH1 with acompound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: A isoptionally substituted cycloalkyl, aryl, or heterocycle; X is a bond,—O—, —S—, —C(O)—, —C(R₄)═, ═C(R₄)—, —C(R₃R₄)—, —C(R₄)═C(R₄)—, —C≡C—,—N(R₅)—, —N(R₅)C(O)N(R₅)—, —C(R₃R₄)N(R₅)—, —N(R₅)C(R₃R₄)—, —ONC(R₃)—,—C(R₃)NO—, —C(R₃R₄)O—, —OC(R₃R₄)—, —S(O₂)—, —S(O₂)N(R₅)—, —N(R₅)S(O₂)—,—C(R₃R₄)S(O₂)—, or —S(O₂)C(R₃R₄)—; D is optionally substituted aryl orheterocycle; R₁ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₂ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₃ is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionallysubstituted alkyl; R₄ is hydrogen, alkoxy, amino, cyano, halogen,hydroxyl, or optionally substituted alkyl or aryl; each R₅ isindependently hydrogen or optionally substituted alkyl or aryl; and n is0-3.
 182. (canceled)
 183. (canceled)
 184. (canceled)
 185. A method oftreating, preventing or managing irritable bowel syndrome in a patient,which comprises inhibiting TPH1 activity in the patient. 186-193.(canceled)
 194. A method of treating, preventing or managing agastrointestinal disease or disorder, which comprises administering to apatient in need of such treatment, prevention or management atherapeutically or prophylactically effective amount of a potent TPH1inhibitor. 195-202. (canceled)